MicroRNA regulation of the immune system

A review of current literature team-written by UCSF graduate students as a final project for the minicourse BMS 270: Small RNA Regulation of the Immune Systerm, 2011.

Gabriel Reyes, Marie LaRussa, Timothy Schmidt, Bevin English, Shoshana Greenberg, Imran Khan, Viola Lam, Allyson Spence, and Elena Zehr

Edited by Nikki Shariat and Lukas Jeker

Course Directors: Michael McManus and K. Mark Ansel


Within the past decade, the field of immunology has increasingly intersected with the field of microRNA (miRNA) biology. While the earliest studies of miRNA function in the immune system have demonstrated an essential role for miRNAs as a whole, recent studies have focused on the contribution of specific miRNAs to specific immunologic processes. In this review, some of the miRNAs, which have been shown to have important functions in the immune system, are highlighted with a focus on their roles in hematopoietic development, cancer, immune homeostasis, and autoimmunity. Such roles include their ability to negatively regulate signaling pathways (see miR-146, miR-155) and transcription factors essential to lineage commitment (see miR-223, miR-150). They play important roles in immune tolerance (see miR-21,miR-155) and it has been shown that development of specific lineages is often dependent on specific miRNAs (see miR-15a/16-1, miR-223). Finally, many immune-related miRNAs regulate growth and apoptosis, leading to their high frequency of association with hematologic malignancy.



Over the past decade, the importance of microRNAs for regulation of cell behavior has become more and more apparent. In the field of immunology, these small but potent regulators are starting to be appreciated for their role in a range of processes, including hematopoietic development, immunity, and malignancy (see Figure 1). miRNAs are small (~22 nucleotide), noncoding RNAs that bind to their cognate mRNAs via a recognition sequence called the “seed sequence,” which is the 2nd-8th nucleotides of the miRNA1. This binding can trigger mRNA destabilization, leading to a decrease in the protein products encoded by their cognate mRNAs.

Although a given miRNA may only modulate the protein level of a target mRNAs by small amounts (usually less than 2-fold), it may have a powerful effect on the overall function of the cells in which it acts. One reason for this is that miRNAs tend to be highly pleiotropic, with a given miRNA having several target mRNAs. Thus, a miRNA can target several members of a given signaling pathway or different targets in converging pathways to have a large effect upon the cell. Also, in systems where cell function is highly responsive to the dosage of a given protein, even a small change in protein level can have a large impact.  In addition, miRNAs tend to be highly redundant, with multiple individual miRNAs converging upon the same target mRNAs. Such miRNAs are often in the same miRNA “family”, with members sharing identical or highly similar seed sequences.

Recently, the role of miRNAs in specific immune cells has begun to be appreciated. Since complete knockouts of Dicer, a protein essential for miRNA biogenesis2, lead to lethality early in development3, initial forays into the role of miRNAs in immunology focused on knocking out Dicer using a conditional Cre/lox system. Specific deletions of Dicer in the T cell lineage resulted in defective T cell development and irregular T helper cell differentiation and cytokine production4, although Dicer did seem to be dispensable for CD4/8 lineage committment5. Further studies into the role of microRNAs in regulatory T (T reg) cells showed that miRNAs are necessary for proper T cell function, as mice lacking miRNAs in their T reg compartment developed a fatal systemic autoimmune disease6-8.

While these initial studies were informative as to the role of miRNAs globally in specific cell types, later studies have started to focus on the role of specific miRNAs and their role in cell regulation. In this review, the roles of nine different miRNAs or miRNA clusters in hematopoietic development, immunity, and cancer are described. While this list is not exhaustive, the miRNAs chosen are illustrative of recent work in the field of miRNA regulation of immune processes. Through a deeper understanding the role of each of these miRNAs in the immune system, insight into their mechanisms of action can be gained, potentially opening the door to new miRNA-based therapies.



Recent work has implicated miR-146a in the regulation of innate and adaptive immunity, the inflammatory response, autoimmunity and cancer. miR-146a negatively regulates the acute innate immune response following activation through pattern-recognition receptors and by pro-inflammatory cytokines9,10. miR-146a was shown to be highly expressed in the human monocytic THP-1 cell line in response to LPS stimulation or treatment with the pro-inflammatory cytokines TNF-α or IL-1β9. The miR-146a promoter contains several binding sites for NF-κB and induction of miR-146a in response to TLR signaling is dependent on NF-κB11. miR-146a has been shown both in vitro and in vivo to target IRAK1 and TRAF6 and to thereby suppress the expression of NF-κB’s target genes such as IL-6, IL-8, IL-1β and TNF-α12-16. Viral infection of murine macrophages with vesicular stomatitis virus (VSV) induces miR-146a to negatively regulate the RIG-I antiviral pathway by targeting Irak1, Irak2 and Traf6 and in doing so suppressing the production of type-I interferon15. miR-146a also targets STAT-1 and IRF-5, both of which are involved in the type I interferon response pathway16. Interestingly, low levels of miR-146a in lupus patients correlate with higher levels of interferon and with worse clinical disease16. Together, these studies depict an extensive role for miR-146a as a negative regulator of pro-inflammatory signaling in innate immunity and suggest an association with autoimmune disease.

Several studies have also focused on miR-146a’s role in endotoxin-induced tolerance. Endotoxin tolerance is the hyporesponsive state of monocytes to subsequent LPS challenge following a prolonged period of LPS exposure. This tolerance is necessary to prevent aberrant inflammation due to continuous exposure to bacterial components such as commensal flora at epithelial surfaces. Experiments with THP-1 cells have shown that miR-146a levels increase following LPS exposure and negatively correlate with TNF-α levels as the cells develop a state of LPS tolerance14. Importantly, tolerance induction requires miR-146a upregulation, and the transfection of miR-146a is sufficient to induce endotoxin tolerance even in the absence of LPS-priming14. Subsequent work confirmed these findings and showed that miR-146a was necessary for LPS-induced cross tolerance to several different TLR ligands17. Furthermore, miR-146a is important for innate immune tolerance in the neonatal intestine because it targets IRAK1 and thereby prevents apoptosis of intestinal epithelial cells following exposure to bacteria9. These studies demonstrate miR-146a’s key role as a negative feedback regulator to prevent uncontrolled inflammation in response to persistent bacterial exposures such as commensal flora.

Consistent with this theme, treatment of A549 lung epithelial cells with high levels of IL-1β rapidly increases miR-146a and suppresses the IL-1β-induced chemokines IL-8 and RANTES9. Furthermore miR-146a is constitutively expressed at high levels in non-activated Langerhans cells (LCs) in the epidermis when compared to interstitial dendritic cells in connective tissues18. The transcription factor PU.1 induces miR-146a in response to TGF-β1 signals in the epidermis, and miR-146a increases the activation threshold for LCs in response to TLR2-dependent activation. Taken together, these findings support a role for miR-146a to negatively regulate the innate immune response in epithelial surfaces and suggest a mechanism for inducing innate tolerance to commensal flora.

In addition to its role in innate immunity, miR-146a is also known to play an important role in the adaptive immune response. miR-146a expression is higher in Th1 cells and lower in Th2 cells when compared to naïve T cells, suggesting that miR-146a may be involved in the lineage differentiation of lymphocytes19. Furthermore, miR-146a can inhibit LPS-induced production of IFN-γ and iNOS by T cells20. miR-146a is also highly expressed in both effector and central memory T cells and is induced in naïve T cells upon TCR stimulation in a calcineurin-, NF-κB- and c-ETS-dependent fashion21. Interestingly, miR-146a can target FADD and potentially modulate activation-induced cell death (AICD) in T cells21. Furthermore, miR-146a overexpression in T cells was shown to impair the TCR-dependent increase in AP-1 activity and production of IL-222. There have also been reports of increased miR-146a levels in both synovial tissues and in PBMCs of rheumatoid arthritis patients12,22, suggesting that miR-146a may promote the survival of self-reactive T cells in autoimmunity.

More recent work has utilized a mouse model with targeted deletion of miR-146a to further elucidate its role in innate and adaptive immunity. Use of this model concluded that miR-146a is highly expressed in Tregs and is essential for Treg suppressor function in vivo23. Deficiency of miR-146a in Tregs leads to a fatal breakdown of tolerance and results in Th1-mediated immunopathology that is dependent on IFN-γ. Furthermore, miR-146a’s targeting of Stat-1 is necessary for the in vivo suppressor function of Tregs23. T effector subsets were also deficient for miR-146a in this model and were shown to produce higher levels of IFN-γ and to contribute to the pathogenic Th1 response. Further work utilizing lineage-specific ablation of conditional alleles is necessary to clearly define the role of miR-146a in different lymphocyte subsets.

The miR-146a knockout mouse was also used to validate miR-146a’s role in regulating innate immunity13. In addition to developing autoimmunity, these mice are hyperresponsive to LPS and demonstrate an exaggerated pro-inflammatory response when challenged with endotoxin. Furthermore, aged knockout mice develop tumors in their secondary lymphoid organs and undergo myeloproliferation, suggesting that miR-146a regulates proliferation in immune cells13,24. Consistent with this latter finding, miR-146a-deficient mice develop myeloid malignancies due to chronic dysregulation of NF-κB signaling24.

Interestingly, miR-146a-deficient mice develop many of the same abnormal hematopoietic phenotypes described in a subset of myelodysplastic syndrome (MDS) patients with 5q- syndrome in which a segment of chromosome 5q is deleted. This observation is relevant because miR-146a resides on chromosome 5q33.3 and because miR-145 and miR-146a expression is reportedly lost in the CD34+ bone marrow cells of many MDS patients with 5q- syndrome25. In addition, in vitro knockdown of miR-146a in mouse hematopoietic stem/progenitor cells can recapitulate many of the phenotypic abnormalities observed in 5q- syndrome25. Together, these studies suggest a role for miR-146a as a tumor suppressor and in controlling the proliferation of immune cells.



miR-223 is preferentially expressed in hematopoietic cells, primarily in myeloid cells in both mice26 and humans27,28. Interestingly, overexpression of miR-223 in mouse hematopoietic progenitor cells leads to an increase in T-lymphoid lineage cells, as identified by the Thy-1.2 marker26. However, much of the research on miR-223 has focused on its role in myeloid cell differentiation. miR-223 expression in the mouse myeloid compartment increases during granulocyte differentiation, with the highest expression level found in peripheral blood neutrophils29. Surprisingly, miR-223 knockout mice have higher levels of granulocytes and their progenitors compared to wild type and develop spontaneous inflammatory lung pathology. This cell-autonomous expansion of the granulocyte progenitor population is likely due in part from the dysregulation of one of the miR-223 targets, the transcription factor Mef2c, as myeloid-specific ablation of Mef2c in miR-223 knockout mice rescued the neutrophilia phenotype. In addition to an expanded granulocyte compartment, loss of miR-223 also results in hypermature granulocytes, and this phenotype is not rescued by loss of Mef2c, suggesting that miR-223 regulates granulocyte function through other targets that have yet to be identified29. In addition to proper granulocyte differentiation and function, miR-223 is also essential for proper erythroid development. Overexpression of miR-223 in the human leukemia cell line K562 has been shown to reduce cell proliferation30 and erythroid differentiation but to promote megakaryocytic differentiation, as measured by the abundance of 4N cells31. miR-223 likely controls erythrocyte development in part by directly targeting LMO2, an important regulator of hematopoiesis30,31. Additionally, miR-223 also directly regulates FBXW7, which regulates the cell cycle by inducing cyclin E ubiquitination and subsequent degradation32. Mice with impaired Fbw7-mediated control of cyclin E have increased levels of erythroid precursors, suggesting that miR-223 may regulate erythrocyte development through FBXW7 as well as LMO2. Finally, miR-223 is also expressed in resting NK cells and decreases upon activation. Downregulation of miR-223 may be important for proper activation of NK cells, as GzmB, the gene encoding granzyme B, is a direct target of miR-22333.

While the regulatory roles of miR-223 have been investigated in several lineages, the regulation of the miRNA itself has also been explored. In a human acute promyelocytic leukemia cell line, there exists a regulatory network involving the transcription factors NFI-A and CEBPa wherein NFI-A ensures low levels of miR-223 transcription in progenitor cells by binding approximately 700bp upstream of pre-miR-223. After retinoic acid treatment, which induces differentiation, CEBPa outcompetes NFI-A for binding to the miR-223 promoter and drives higher expression of miR-22334. miR-223 subsequently targets NFI-A, creating a regulatory loop that enforces the differentiation signal. However, Fukao et al. propose an alternative mechanism for miR-223 regulation, suggesting that miR-223 is derived from a much longer transcript, placing the CEBPa /NFI-A promoter region in the second intron of the pri-miRNA. In this alternative mechanism, the transcription factors PU.1 and C/EBP, which are both essential for myeloid differentiation, are necessary for proper pri-miR-223 transcription, while GATA-1, which is essential for erythroid development, represses miR-223 expression35. There is evidence of the predominant role of the PU.1/CEBP promoter region in pri-miR-223 transcription36, but the exact role of the intronic NFI-A/CEBPa region remains unclear. Thus, further studies investigating the roles of each of these regulatory regions are needed.

Because of its important role in the differentiation and proliferation of different hematopoietic lineages, it is not surprising that miR-223 has been implicated in leukemia. In particular, miR-223 is important in acute myelogenous leukemia (AML), which is not surprising given the essential role of miR-223 in myeloid differentiation. The mechanism behind the dysregulation of miR-223 is still an area of active investigation, though recent advances have been made. The AML1/ETO fusion oncoprotein, the most common chromosomal translocation in AML, represses pri-miR-223 transcription, contributing to the block in myeloid differentiation in AML blasts37. Additionally, research into the role of miR-223 in AML has helped further elucidate the miRNA’s role in normal development. MiR-223 directly targets E2F1, a transcription factor necessary for proper cell-cycle progression, ultimately resulting in proper granulocytic differentiation. However, downregulation of CEBP that often occurs during AML, either through oncoproteins or through CEBP mutations, leading to a downregulation of miR-223, and ultimately resulting increased levels of E2F1. E2F1 overexpression then results in further repression in miR-223 in a negative feedback loop, ultimately contributing to the failure of myeloid differentiation38.

In short, miR-223 is an essential factor for hematopoiesis, particularly in the myeloid compartment, and some of its direct targets essential in this process have been identified. However, there are likely other targets that still remain unknown, and the mechanisms governing miR-223 expression itself still must be clarified. Proteomics work has identified proteins that are significantly more abundant in neutrophils from miR-223 knockout mice as compared to wild type, and subsequent in silico analysis confirmed that at least 78 of the genes encoding these proteins contain at least one potential miR-223 binding site in their 3’ UTRs. Further, some of these genes are known to be involved in neutrophil maturation and immune function39. However, these putative targets still must be validated as direct targets of miR-223. Thus, much work remains in identifying both the targets of miR-223 and the mechanisms of miR-223 regulation. And understanding the biology of the miR-223 will likely contribute to our knowledge of the pathology behind many types of cancer, especially leukemia.



The best understood role of miR-150 in the hematopoietic system is its regulation of the transcription factor Myb during B cell development. It is becoming clear, however, that miR-150 has additional relevant targets that affect growth, maturation, and the immune response in both B and T lymphocytes, and that downregulation of miR-150 in lymphatic tissue results in unregulated proliferation that contributes to tumorigenesis.

miR-150 was first identified as having a role in immune system regulation during microRNA profiling of the hematopoietic system of mice, where it was found to be differentially expressed in lymphocytes19. miR-150 levels are high in the lymph nodes and spleen and detectable in the thymus, heart, and brain. Further characterization established that miR-150 is upregulated in mature, resting B and T cells and strongly downregulated in their precursors and upon activation 19,40,41.

miR-150 null mice appear normal; however, they possess a higher ratio of splenic and peritoneal B1 cells and show a significant increase in the production of “natural” antibodies (predominantly expressed by B1 cells and present in the serum of individuals without known prior exposure to the corresponding antigen)41. Overexpression of miR-150 in hematopoietic stem and progenitor cells as well as ectopic expression of miR-150 at physiological levels during embryonic development both result in a phenotype opposite to that of the knockout mice. Mice still appear normal, but show greatly impaired B cell development and mildly impaired T cell development. B cell maturation in these models is blocked at the pro-B to pre-B stage, and the number of B1 cells is greatly reduced40,41. These defects in B cell maturation are attributed to the aberrant expression of Myb, a major target of miR-150.

The transcription factor and proto-oncogene Myb regulates many aspects of lymphocyte development and is required for proliferation and survival of immature hematopoietic cells42. Myb was confirmed as a direct target of miR-150 using in vitro. In addition, employing both loss and gain-of-function of miR-150 in transgenic mice, combined with partial or full loss of Myb, has confirmed Myb as a target of miR-150 in vivo41. The expression pattern of Myb in B cells inversely correlates with that of miR-150: it is highly expressed in progenitor cells, downregulated in mature B lymphocytes, and upregulated again after activation. Furthermore, in cell lines and transgenic mice, a deletion of Myb phenocopies miR-150 overexpression, and vice versa. Regulation of Myb by miR-150 is therefore thought to account for miR-150’s effects on B cell development. Premature downregulation of Myb by miR-150 triggers apoptosis during the pro-B stage while upregulation of Myb in miR-150 null mice triggers aberrant proliferation41. Taken together it seems that miR-150-mediated downregulation of Myb is required during the pre-B to mature B cell transition in order for it to occur.

Myb is known to be involved in a multitude of hematopoietic processes, including T cell, myeloid, and erythrocyte development, so it is unclear why miR-150 expression produces a Myb-dependent defect predominantly in B cells. It is likely that additional, unidentified targets of miR-150 contribute to the observed B cell-specific phenotype. Although not mediated through Myb regulation, aberrant expression of miR-150 also affects T cell development.  miR-150 was found to be strongly upregulated during T cell maturation; its expression is low in precursor double-negative T cells, moderate in double-positive and CD8+ cells, and high in CD4+ cells40,43. Recently a new target of miR-150 was identified that might be involved in miR-150-mediated control of T cell maturation. Notch3, a membrane receptor that plays an important role in T cell differentiation and leukemogenesis, was found to have a binding site for miR-150 on its 3’ UTR and to have expression patterns in T cells that are opposite to those of miR-150. Luciferase reporter assays and overexpression of miR-150 in T-cell acute lymphoblastic leukemia (T-ALL) cell lines confirmed Notch3 as a target of miR-150. Downregulation of Notch3 in these cell lines by overexpressing miR-150 increased apoptosis and reduced proliferation43. Notch signaling is necessary for T cell lineage commitment, particularly at the T versus B lymphoid decision, so downregulation by miR-150 after linage commitment might be necessary to stop proliferation and induce maturation. 

Consistent with its growth-restrictive role in T-ALL cell lines, miR-150 expression was found to be downregulated in lymphoma cell lines and tissues. Transducing miR-150 into NK/T-cell lymphoma cells caused increased apoptosis, decreased proliferation, and enhanced senescence. miR-150 was found to directly target AKT2 (a signal transducer in the PI3K pathway) and DKC1 (a snoRNP related to telomerase function whose loss is associated with senescence) and cause higher expression levels of Bim and p53 (both with pro-apoptotic functions), indicating that it likely behaves as a tumor suppressor in lymphoma44. miR-150’s primary target, Myb, is oncogenic in many systems and as such may also contribute to miR-150’s role as a tumor suppressor. It is likely that one of the main functions of miR-150 in lymphocyte development is to restrict proliferation during specific stages of maturation in order to allow proper development. This is in agreement with the observation that downregulation of miR-150 confers a growth advantage in transformed lymphocytes. Importantly, a proper immune response also requires downregulation of miR-150 after activation of mature B and T cells in order to releases them from growth arrest and allow rapid proliferation to occur.



The microRNA miR-181 is involved in the pathogenesis of many types of cancer and it plays an important role in the adaptive immune system. miR-181 consists of a family of micro-RNAs that include miR-181a, b, c, and d. miR-181a and b are clustered together on mouse chromosome 8, and miR-181c and d are clustered together on mouse chromosome 2. miR-181 is expressed in many tissues, but it is enriched in the hematopoietic lineage: in T and B cell precursors in mice26,45as well as B and T cell precursors, monocytes, and granulocytes in humans27. The miR-181 family members are involved in regulation of both B and T cells and their differential expression is important in maintaining normal function and development of these cell types. 

It is thought that miR-181 acts independently in the T and B cell lineages, performing different functions in each. miR-181 acts as a positive regulator of B cell development; overexpression in bone marrow cells increases the number of CD19+ B cells, decreases CD8+ T cells, and slightly decreases CD4+ T cells and Mac1+/Gr1+ myeloid cells26. One of the miR-181 family members, miR-181b, impairs class switch recombination (CSR) when expressed in activated B cells, resulting from the down-regulation of its target, activation induced cytidine deaminase (AID)46. This regulatory mechanism of AID can be relevant to prevent B cell malignant transformation46.

Another miR-181 family member, miR-181a, plays a well-established role in development of T cells. In T cell precursors, mainly double negative (DN) and double positive (DP) cells, miR-181a expression is highly upregulated, while in single positive (SP) and mature T cells miR-181a expression is very low45. This dynamic regulation of miR-181a expression in T cell precursors suggests that miR-181a may play a role in development of T cells in the thymus. Indeed, it has been shown that miR-181a is involved in regulating T cell receptor (TCR) signaling by increasing the receptor sensitivity and signal strength via modulating intracellular signaling cascades. miR-181a can bind to and down-regulate multiple phosphatases, including Src homology 2 domain-containing protein-tyrosine phosphatase (SHP)-2, protein-tyrosine phosphatase (PTP)-N22, and the ERK-specific, dual specificity phosphatases (DUSP)-5 and DUSP-6. Decreases in the levels of these phosphatases leads to an increase in phospho-ERK as well as other intracellular signaling molecules and an increase in TCR signaling.  miR-181a helps to increase clonal deletion of specific moderate-affinity T cells through modulation of the TCR signaling threshold47, which increases the efficiency of both positive and negative selection in the thymus45 and could work to prevent autoimmune disease.

A third miR-181 family member, miR-181c, has the same seed sequence as miR-181a, but is different at one nucleotide in the loop region, and does not have similar activity in development of DP T cells. The distinct difference in activities between these two miRNAs may be determined by their unique pre-miRNA loop nucleotides48. Mutations in pre-miRNA loop regions affects processing of these miRNAs; the nucleotides at the 5’ and 3’ ends as well as the pre-miRNA loop are critical for the activity of miR-181a48. These differences in loop structure may give miR-181a and miR-181c their own, separate functions, indicating that miRNAs encoding identical or nearly identical mature miRNAs could exert different biological activities as determined by their unique loop nucleotides48. However, unlike miR-181a, miR-181c does have activity in activated CD4+ human T cells49. Overexpression of miR-181c partially impairs CD4+ T cell activation through its targeting of IL-2, which is normally upregulated in activated T cells.  This down-regulation of IL-2 leads a reduction in proliferation of the T cells49.

Expression patterns of miR-181 are also altered during autoimmune disease, which is not surprising considering the role of miR-181a in T cell selection. In pediatric Systemic Lupus Erythematosus (SLE) patients, who have a chronic, multi-organ autoimmune disease, miR-181a is significantly down-regulated. p300-CBP associated factor (PCAF), a target of miR-181, is upregulated in SLE patients compared to healthy controls, which leads to increased p53 expression and apoptosis in these cells50. This suggests that miR-181 may be playing an important role in SLE pathogenesis. 

Altered expression of miR-181 has been shown in many types of cancer. In aggressive B cell chronic lymphocytic leukemia (B-CLL) with chromosomal deletion of 11q, miR-181 is downregulated, suggesting some regulatory requirement for this part of the genome in miR-181 expression. In aggressive B-CLL without the chromosomal deletion, miR-181 is highly expressed51. T cell leukemia/lymphoma (Tcl1) is an oncogene that is upregulated in T cell leukemia and can be the causal oncogene in B-CLL. It is inhibited by miR-181b51, suggesting that miR-181 plays a role in cancer prevention in these types of leukemia. In multiple myeloma, miR-181 binds PCAF, which is critical to disease pathogenesis. Upregulation of miR-181 can lead to repression of PCAF, which involves an increase in tumors because of PCAF’s effect on p5352. Cytogenetically normal acute myeloid leukemia (CN-AML) also involves altered miR-181 expression53; the high risk group of patients has an upregulation of miR-181a and b that is inversely associated with risk of death or relapse54. There are many studies that show the influence of miR-181 in cancer51-55, both in cancers of the hematopoietic system, as well as breast, pancreatic, and prostate cancers55.



In 2006, Equela-Kerscher and Slack coined the term oncomiRs referring specifically to the set of microRNAs capable of acting like oncogenes or tumor suppressor genes.  Since this time, known oncomiRs, such as the miR-17~92 cluster, have been identified. One such oncomiR, miR-21, was identified as being significantly overexpressed in glioblastoma multiforme (GBM) patients as well as GBM cell lines56. Since then, miR-21 overexpression has been seen in a wide range of solid tumors such as breast, lung, colon, gastric and pancreatic. miR-21 is also upregulated in leukemia (CLL, AML) and lymphomas (DLBCL, Hodgkins)57. Recent work suggests that in the HL60 cell line miR-21 overexpression halted differentiation induced by PMA and led to increased proliferation of these cells, suggesting a role for miR-21 in driving cell division57. In 2008, one group identified PTEN, a known tumor suppressor, as a target of miR-21 in Cowden syndrome58. Others have found overexpression of miR-21 may result in a decrease of another target PDCD4, a known tumor suppressor gene associated with poor prognosis in lung and colorectal cancers57. Taken together, one could speculate that an activation of the PI3K pathway, due to loss of PTEN, may contribute to the increased proliferation of cells overexpressing miR-21. In addition, miR-21 is activated in response to the presence of oncogenic Ras both in vitro and in vivo59. In such a short period of time, mounting evidence suggests a role for miR-21 in solid tumors, leukemia, and lymphomas. 

Within the past three years much work has been done to further elucidate the role of miR-21.  A microRNA signature in Tregs was identified in 2009, which included mir-21, and mir-31. These two miRNAs have a role in altering the levels of FoxP3, a transcription factor and master regulator in the development of regulatory T cells60. miR-31 was shown to decrease FoxP3 through direct targeting of the 3’UTR while miR-21 acted to increase levels of this transcription factor.  Aside from having a role in adaptive immunity, miR-21 was also identified as being capable of influencing the inflammatory response in macrophages. More specifically, miR-21 regulates this process through direct 3’UTR targeting of the tumor suppressor PDCD461. Their data suggests that induction of miR-21 following exposure to lipopolysaccharide (LPS) was dependent on transcription via the pro-inflammatory protein, NF-κB. Following LPS stimulation of miR-21, PDCD4 was decreased. Following LPS stimulation, PDCD4 was decreased, however this inhibition was abrogated through the use of a miR-21 antagomir. In mice lacking PDCD4, LPS stimulation resulted in increased anti-inflammatory cytokine IL10. Ultimately, they propose miR-21 decreases PDCD4 levels, which results in a regulation of the LPS induced inflammatory response. 

A unique set of experiments related to miR-21 function in recent years was the proposal of oncomir addiction. Until now, oncogene addiction has been studied extensively as a way of understanding how cells become rewired in the context of a deregulated protein able to confer a proliferative advantage. In 2010, Medina et al demonstrated the first example of oncomir addiction in a mouse model. miR-21 expression was limited to the hematopoietic compartment through a conditional expression system62. Following two months of miR-21 overexpression wild type and NOD/SCID transplanted mice developed hematologic malignancies as characterized by massive lymphadenopathy, lower limb paresis, hunched posture, labored breathing and splenomegaly. Immunophenotyping (IgM- CD3- B220+) suggested a precursor B-cell lymphoblastic lymphoma/leukemia. Loss of miR-21 expression resulted in massive apoptosis, complete tumor regression and a 100% survival rate. This indicates the importance of miR-21 in not only the induction but also the maintenance of this malignancy. This was the first example of a microRNA acting as the sole oncogenic lesion behind malignant transformation whose presence is required for tumor maintenance. This will undoubtedly spark further interest in identifying a potential mechanism for microRNA inhibition as cancer therapy. miR-21 displays a diverse set of functions in the immune system, ranging from Treg development through FoxP3 regulation. It also has a role in fine-tuning the balance between a pro-inflammatory and anti-inflammatory state and seems to have a vital role as an oncomir, similar to other well-studied microRNAs.


miR-17~92 cluster

Thus far, studies of the miR-17~92 cluster have shown it to be an incredibly potent promoter of tumor survival. In addition, this cluster is essential for proper development and cell fate decisions in the T and B cell compartment. Many of these effects have been tied to predicted and/or verified targets of various miR-17~92 cluster members, which are enriched for targets controlling cell differentiation, cell cycle, response to DNA damage stimulus, and apoptosis63.

The mirR-17~92 cluster is composed of six members from four different seed families, which are transcribed in a polycistronic fashion before being processed into individual cluster members. In humans, the six miRNAs of this cluster (miR-17, miR-18a, miR-19a, miR-20a, miR-19b-1, and miR-92-1) are found close together in an 800bp region in the 3rd intron of the primary transcript C13orf25 on chromosome 1364. miR-17 and miR-20a share the same seed sequence, as do miR-19a and miR-19b-1. The sequences and organization of these various miRNAs in the miR-17-92 cluster is strongly conserved in all vertebrates. Gene duplication events have led to the existence of two other cluster paralogs in mammals: miR-106b~25 and miR-106a~363 cluster, located on human chromosome 7 and the X chromosome, respectively. These clusters are not completely redundant, as individual miRNA duplication or deletion events have led to gain or loss of certain miR-17~92 paralogs65.

During normal development, the miR-17~92 cluster most notably plays a role in heart, lung, and B cell development. miR-17~92-deficient mice die within minutes after birth and exhibit lung hypoplasia and ventricular septal heart defects65. In addition, these mice had a greatly reduced percentage and absolute number of pre-B cells due to increased apoptosis in this compartment. This study also showed that miR-17~92 plays a critical role in promoting the survival of early B cell progenitors during adult B cell development. It appears that the increased in apoptosis seen in the miR-17~92-deficient mice was due in part to increased expression of the proapoptotic protein Bim, which is a direct target of the miR-17~92 cluster. When miR-17~92-deficiency was combined with loss of both paralogous clusters (miR-106b-25 and miR-106a-33), developmental defects observed in the miR-17~92-deficient mice were magnified, suggesting that there is a functional cooperation between these clusters during embryonic development. When the miR-17~92 cluster is overexpressed specifically in the T and B cell compartments, mice developed an autoimmune disease, characterized by an increased CD4+ T cell population, increased lymphocytes in the periphery, and massive infiltration of lymphocytes into non-lymphoid tissues66.

The miR-17~92 cluster has been most well studied for its role in a variety of cancers, including B cell lymphomas and Acute Myeloid Leukemia (AML) as well as several other types. Overexpression of this cluster acted with the transcription factor c-Myc and led to accelerated tumor growth and higher mortality rates in a model of B cell lymphoma4. Tumors from these miR-17~92-overexpressing mice were also characterized by a lack of the apoptosis normally present in c-Myc-induced lymphomas. Further dissection of the miR-17~92 cluster has shown that miR-19 is a key oncogenic component of the miR-17~92 cluster, and that the oncogenic activity of miR-19 is due in part to its repression of the tumor suppressor Pten68,69.  In addition to its role in suppressing tumor cell apoptosis, the miR-17~92 cluster has recently been found to inhibit oncogene ras-induced senescence via miR-17 and miR-20a targeting of p21WAF1, an inhibitor of cell proliferation and a promoter of senescence70.

Studies of AML containing an MLL rearrangement have revealed the important role that miR-17~92 cluster members can play in promoting tumorigenesis in this disease. AML containing an MLL rearrangement is a leukemia in which the MLL (mixed lineage leukemia) gene undergoes chromosomal translocation and fuses with the 5’ end of other loci, creating chimeric transcripts. Large-scale genome-wide studies have shown that the miR-17~92 cluster is frequently overexpressed in MLL-rearranged AMLs71. It was found that MLL can bind to the miR-17~92 cluster and promote its transcription, and that MLL fusions that occur in MLL-rearranged AML more strongly promote expression of the cluster and thus its tumor-promoting properties63.

Recently, it has been found that the miR-17~92 cluster plays a role not only in cell-autonomous tumor survival, but also in tumor evasion of the immune system. Myeloid-derived suppressor cells (MDSCs) are a major component of the immune suppressive network, and expression of the transcription factor STAT3 induces expansion of MDSCs and suppresses activation of CD4+ and CD8+ T cells in tumor-bearing mice72. STAT3 is a direct target of both miR-17-5p and miR-20a, and tumor-associated factors can downregulate expression of these miRNAs in MDSCs73. Thus, tumor-associated factors serve as an indirect activator of STAT3 by repressing their repressor, which leads to proliferation of MDSCs and increased CD4+ and CD8+ T cell suppression by these cells. This pathway offers an attractive target in the development of cancer immunotherapies.

Studies of the regulation of the miR-17~92 cluster and its targets have revealed that this cluster is directly activated by c-Myc binding to the miR-17~92 locus74. Several E2F family members, which are essential regulators of the cell cycle and apoptosis, are direct targets of the miR-17~92 cluster. Furthermore, E2F1, E2F2, and E2F3 directly bind to the promoter of the miR-17~92 cluster and activate its transcription, creating an autoregulatory feedback loop between miR-17~92 cluster members and E2F family members75

Future investigations into the intricacies of the miR-17~92 cluster’s function will not only offer an enriched understanding of cell regulation, but also possible avenues of therapy against autoimmune disorders and cancer. The miR-17~92 cluster has acquired the name Oncomir-1 for its contribution to various types of cancer. Still other miRNAs, such as miR-155, have proven to have a myriad of roles in both tumorigenesis as well as normal lymphocyte development and function. 



miR-155 has emerged as an important and pleiotropic regulator of both immunity and cancer. In mice, early overexpression of miR-155 in the B cell lineage causes a pre-B cell proliferation that progresses to a lethal B cell malignancy76. Loss of miR-155 - via deletion of the gene, Bic, that encodes it - results in defects in adaptive immunity77-80. In humans, increased expression of miR-155 has been associated with a number of hematologic malignancies, including Hodgkin lymphoma, diffuse large B cell lymphoma, natural killer cell lymphoma, and acute myelogenous leukemia81-83. These observations have motivated study into miR-155’s expression, regulation, and effects in various contexts of immunity.

miRNAome-wide studies show expression of miR-155 is most frequent among cell types of the hematopoietic compartment in human and mouse84. Despite its presence in hematopoietic stem cells and developing lymphocytes, miR-155 is not essential for grossly normal hematopoiesis77. miR-155 expression is highest in activated cells, such as germinal center B cells and skewed T helper cells85. These facts, in combination with the observations from the genetic models, imply that miR-155 is essential for proper regulation of mature leukocytes. In addition, it has been suggested that granulocyte/monocyte precursors in the bone marrow may respond to systemic LPS by upregulating miR-155 to drive a proliferative response to infection83.

Current understanding of the regulation of miR-155 expression supports the idea that activating signals are crucial. Danger signals, including both TLR and interferon signaling, can upregulate miR-155 expression. TLR ligands poly(I:C) and LPS - acting on TLRs 3 and 4, respectively - have been shown to induce miR-155 expression in innate cell models, including mouse primary macrophages, a mouse macrophage cell line, and human monocyte-derived dendritic cells86-88. Interferons and TNF-alpha have also been shown to induce miR-155 in various cell types86,89. On the adaptive side, T and B cell receptor engagements have been associated with upregulation of miR-155, though these effects may be due to autocrine production of cytokines90-92. Indeed, it appears likely that these signals converge to regulate miR-155 expression. The JNK/AP-1 axis is likely the relevant regulator downstream of TLR and B cell receptor signaling86,92. NFkB, which also has a putative binding site in the miR-155 promoter, may also induce expression93.

miR-155’s validated targets implicate it in the regulation of cell growth and survival as well as immune function. SHIP1 is one such protein that has emerged as an important target87,94. SHIP1 is an inositol phosphatase that catalyzes the dephosphorylation of PIP3 to PIP2. Thus, it antagonizes growth factor-related signals that go through Akt and PLCg. Dysregulation of these critical signaling pathways would be expected to perturb a wide variety of cell types, including those perturbed in knockout and transgenic mouse models.

A target-function connection may also be seen in the case of c-Maf. c-Maf is a transcription factor that strongly transactivates IL-4 expression in T cells. Thus, c-Maf may play a role in skewing T cells toward the Th2 phenotype. In vivo expression data from the miR-155-deficient mouse as well as an in vitro reporter assay indicate that c-Maf is a target of miR-15577. In accordance, miR-155’s regulation of IL-4 expression has been implicated in the Th2 fate skewing process; in vitro data suggest that miR-155 expression promotes T cell differentiation to the Th1 phenotype77,78. Complementarily, miR-155 may target the IFN-g receptor, which helps antagonize T cell skewing toward the Th2 phenotype95.

Possibly providing an explanation for the phenotype of Dicer-deficient Tregs, miR-155 expression was shown to be driven by the Foxp3 transcription factor6-8,96. In a luciferase assay, Suppressor of Cytokine Signaling 1 (SOCS1) was shown to be a target of miR-155. It is possible that SOCS1 is a relevant target in vivo for Tregs, which need to suppress its expression in order to homeostatically proliferate in response to limiting amounts of IL-2.

In B cells, activation induced cytidine deaminase (AID) has been shown to be targeted by miR-15597,98. Not only were class switch recombination and affinity maturation affected in these studies, but oncogenic Myc-Igh­ translocations were increased in a model of B cell-specific miR-155 loss98. Also, the intrinsic requirement of miR-155 in B cells for a fully functional extrafollicular and germinal center response is suggested to be due to the targeting of the transcription factor Pu.1 by miR-15580.

miR-155 is an intriguing therapeutic target because of its diverse functions, association with cancer, and significant impact in genetic models. However, further cell type-specific and target-specific in vivo studies will need to be performed to understand its role in inflammation and immunity in vivo. One study contributes to this effort by implicating miR-155 in T cell skewing and autoimmunity in experimental autoimmune encephalitis (EAE), a model of multiple sclerosis79. miR-155-deficient mice were shown to be resistant to induction of EAE. This was related to response to antigen and IL-17 production. Furthermore, the EAE dependence on miR-155 was shown to be CD4+ T cell intrinsic, as miR-155-deficient T cells transferred into a lymphopenic mouse failed to effectively induce EAE.

miR-155 has emerged as a central regulator of immunity. Understanding its relevant targets in different cell populations will provide clues as to its functions in various processes – e.g. antigen-presenting cell activation, B cell class switching, T cell fate decision-making, and Treg homeostasis. miR-155’s roles in these cell types may also reveal it to be an Achilles’ heel of cancers that overexpress it.



Chronic lymphocytic leukemia (CLL) and multiple myeloma (MM) are B-cell malignancies. Years of research suggest that transformation of pluripotent hematopoietic stem cells leads to the development of CLL, whereas transformation of committed B-cells is a trait of MM99.

CLL is characterized by a progressive accumulation of a rare population of B cells, CD5+ B-1lymphocytes100. B-1 cells are a part of both innate and acquired immunity, have autoreactive nature and never fully mature to become a part of memory B cell pool101. In more than half of CLL cases, patients have a deletion of 13q14.3 locus.  This region was later defined as a minimal deleted region (MDR), which encompasses the miR-15a/16-1 cluster, the deleted in leukemia 2 gene, DLEU2, and a part of DLEU1 gene100,102,103.  The miR-15a/16-1 cluster encodes miR-15a and miR-16-1, the micro RNAs that have a common seed sequence and 80% complementarity104. miR-15a and miR-16-1 are highly expressed in normal CD5+B cells100. The detailed mechanism of how this genomic abnormality contributes to the development and/or progression of CLL on the molecular level remains to be resolved.

Recent in vivo and in vitro studies support the role of miR-15a/16-1 cluster in CLL pathogenesis. Mice carrying a conditional allele that mimicked the deletion of the miR-15a/16-1 (miR-15a/16-1−/−) showed normal development of B and T cells at early age, but an increase in CD5+B220low population in the peripheral blood and peritoneal cavity by 15-18 months of age. A quarter of miR-15a/16-1−/− population developed CLL by 18 months of age, but survival rates of miR-15a/16-1−/− mice were similar to the wild-type mice during the 20-months observation period. Mice with B cell-specific deletion of miR-15a/16-1 locus also had abnormal CD5+B cell number, which was an age-dependent phenotype. in vitro miR-15a/16-1−/− B cells showed higher proliferative rates and over-expressed genes involved in G0/G1-S phase transition105. As a result, the miR-15a/16-1 locus negatively controls B cell proliferation.

In addition, both miR-15a and miR-16-1 target pro-apoptotic gene products, which are frequently overexpressed in cells of CLL patients. Analysis of BCL-2 expression, and its message stability in mononuclear cells extracted from the blood samples of CCL patients, revealed an inverse correlation between BCL-2 expression and miR-15a or miR-16-1 expression. In vitro studies showed that both miR-15a and miR-16-1 seed sequences are complementary to the 3’UTR of BCL2 mRNA and directly target the product of BCL2106. Furthermore, miR-15a and miR-16-1 were shown to target products of other proto-oncogenes, such as MCL1, WNT3A and CCND1, leading to the cell cycle arrest and apoptosis107,108.

Loss-of-function mutations at 13q14.3 locus are not necessarily sporadic, but can be heritable. A clinical study showed that C to T substitution in the pri-miR-16-1, 7 bases in the 3' direction after the precursor, which on the molecular level is characterized by a significant decrease of miR-16-1 expression, is found in germ-line of 12% of CLL patients examined. Furthermore, immediate relatives of CLL patients are predisposed to the development of CLL with age107. The New Zealand Black (NZB) mouse is the model system to study the development and progression of heritable CLL. Age-associated expansion of CD5+ B-1 autoreactive clones with chromosomal abnormalities and an increased proportion of stem cell population among splenocytes together with the progressive autoimmunity are the major traits of CLL in NZB mice. B cell population derived from NZB mice exhibited a decrease in mature miR-16 due to a point mutation within the mir-15a/16-1 locus. In addition, splenic stem cells from NZB mice were found to contain a larger B-1 stem cell population when compared to pluripotent splenocytes derived from the wild-type cohort. As a result, the presence of a B-1 stem cell precursor explains in vivo age-dependent expansion of CD5+ B-1 population in NZB mice109.

MDR deletion also frequently coincides with MM progression110. A loss-of-function approach was used to characterize the role of miR-15a/16-1 in MM. The miR-15a/16-1 knockout MM cells showed enhanced proliferative, pro-angiogenic and invasive behavior due to upregulation of multiple oncogenes. When a lentiviral system was used to silence the expression of miR-15a/16-1, growth rates of MM cells significantly increased. Inhibition of miR-15a/16-1 activity with a miRNA “sponge” induced metastatic behavior and increased growth rates of MM cells in vivo, causing limb paralysis, bone marrow tumors or a lethal outcome upon their injection in sub-lethally irradiated mice110.

Overall, the miR-15a/16-1 locus has shown to be important for control of cell cycle progression and apoptosis in B lymphocytes. In particular, miR-15a/16-1 downregulates the expression of cyclin-D1, BCL-2 as well as other products of proto-oncogenes. Future studies focusing on direct targets of miR-15a and miR-16-1 in well-studied pathways such as Wnt signaling pathway, should give a better perspective on the exact molecular roles that these two micro RNAs play within B cells. In addition, miR-15a/16-1 seems to play a negative role in the expansion of splenocyte stem cell populations or, even, dedifferentiation of committed B cells into B-1 stem cell populations101. Future studies should focus on the roles of miR-15a and miR-16-1 in each subset of B cells as well as how these small RNAs affect fidelity in commitment to B lymphocyte lineage. In addition, the locus plays a guardian role against autoimmune disorders by preventing expansion of the B-1 cell population. Finally contribution of highly similar loci, such as the one found on 3q25–26.1 that encodes miR-15b and miR-16-2104, is needed to be taken into consideration. Still questions remain to identify if it is indeed haploinsufficiency, or complete loss of function that makes 13q14.3 and not 3q25–26.1vital for B cell division and differentiation, preventing the progression of CLL or MM.



miR-182 is located in the intergenic region of human chromosome 7 and mouse chromosome 6. It is a member of the miR-183-miR-96-miR-182 cluster. miR-182 expression is associated with many types of cancer. In particular, miR-182 has provided diagnostic and prognostic implications in prostate, lung, glioma, and other types of cancers111-113. miR-182 is also expressed in the retina and in the hair cells of the inner ear114-116. However, little is known about miR-182 expression in hematopoietic cells.

Expression of miR-182 is increased in primary myelofibrosis (PMF) patients117. PMF patients have increased collagen-induced fibrosis in their bone marrow resulting in impaired hematopoiesis. PMF is characterized by an amino acid change from valine to phenylalanine at position 617 in exon 14 of JAK2. Elevated miR-182 expression in granulocytes from PMF patients correlates with the mutant JAK2617V>F allele burden. Furthermore, granulocytes and reticulocytes from patients with polycythemia vera (PV), a form of myeloproliferative disease, have increased expression of miR-182118. The cell cycle protein, cyclin D2, is proposed to be a miR-182 target in PV granulocytes. Elevated expression of miR-182 in PV granulocytes correlates with decreased expression of cyclin D2. However, cyclin D2 has not been validated to be a direct target of miR-182.

Since elevated expression of miR-182 is prevalent in cancer, many have shown that miR-182 knockdowns will reduce tumor progression, which suggests that miR-182 is important for cellular proliferation119,120. However, the function of miR-182 in the immune system is largely unknown. Recently, Stittrich et al. reported interleukin 2 (IL-2)-induced miR-182 promotes clonal expansion of activated T cells121. Activation of the T cell receptor (TCR) by antigen binding induces proliferation and IL-2 production by CD4+ helper T cells. Clonal expansion of T cells is dependent on antigen-induced IL-2 production but is then independent of further antigenic stimulation. Using IL-2 and CD25 (IL-2 receptor α chain) blocking antibodies, the authors found decreased miR-182 expression, which suggests that IL-2 induces miR-182 expression. The authors further determined that STAT5, a transcription factor activated by IL-2, directly binds to the regulatory region of miR-182 and induces miR-182 expression. Consistent with previous studies, the authors verified that the transcription factor, Foxo1, is a target of miR-182122. Foxo1 inhibits cell cycle progression; therefore miR-182 targeting of Foxo1 allows cell cycle progression and clonal expansion of activated T cells. Ectopic expression of miR-182 resulted in increased T cell clonal expansion. Inhibition of miR-182 in an arthritis transfer model reduced helper T cell-induced inflammation. Therefore, the authors propose that miR-182 mediates helper T cell clonal expansion at the post-transcriptional level.

Using microarray profiling and subsequent real-time RT-PCR analysis, Dai et al. found high expression of miR-182 in splenic T and B cells from lupus-prone MRL-lpr, B6-lpr, and aged NZW/W mice123. Moreover, B cells express microphthalmia-associated transcription factor (MITF).  In melanoma, MITF and Foxo3 are direct targets of miR-182124,125. These targets inhibit melanoma metastasis by impeding tumor cell migration and triggering apoptosis125. Overexpression of miR-182, common in melanoma, represses Foxo3 and MITF, thereby promoting melanoma progression. In B cells, MITF inactivation results in spontaneous B cell activation and autoantibody production126. Therefore, it is plausible that miR-182 expression in B cells functions to regulate antibody production. Further studies will be helpful to elucidate the role of miR-182 in B cells.

Many miR-182 functional studies focus on its role in cancer. To determine the function of miR-182, investigators utilized overexpression and knockdown models. Ectopic expression of miR-182 is sufficient to promote tumor growth and metastasis in vivo113,119. Knockdown assays using oligonucleotides complementary to miR-182 inhibit tumor growth and increase apoptosis125. Using overexpression and knockdown assay, the transcription factor, Foxo3, and the enzyme, adenylate cyclase type 6, were identified to be targets of miR-182 in liver cancer119. However, the functional relevance of these targets is not known.

miR-182 knock-out (KO) mice were originally generated to study retinal development114. The pre-miR-182 locus is replaced with the neomycin resistance gene flanked by loxP sites. Expression of the other miRNAs in the miR-182 family, miR-96 and miR-183, are not affected by the deletion. KO mice appear normal with no obvious abnormalities, which suggest that retinal development is independent of miR-182114. Immunological studies using miR-182 KO are needed to provide insight into the role of miR-182 in the immune system.



The mammalian immune system has incorporated and evolved with miRNAs in order to orchestrate the complex network of gene regulation necessary for immunity. Such a broad range of miRNA functions in the immune system makes these miRNAs attractive therapeutic targets. Certainly, those miRNAs that have been demonstrated to be necessary for normal leukocyte function could potentially be antagonized to produce a more specific and moderate immune suppression. In cancers of hematologic cells, dependence on the overexpression of specific miRNAs for survival could provide a new avenue of therapeutic attack. As systems designed to deliver drugs that mimic or antagonize miRNAs emerge, there will likely be a rush to investigate modulation of expression of immune-relevant miRNAs in models of immunologic and malignant disease.

Basic immunology will benefit from the increasing understanding its miRNAs’ roles as well. Since miRNAs are able to regulate multiple targets and are often expressed exclusively in specific cells or cell types, discovering their relevant targets will provide a hit list of other molecules to investigate in the context of immunity. With the golden age of massively parallel, “-omics” techniques upon us, finding the most relevant targets will hopefully become less of a challenge. Also, miRNAs, like transcription factors, play a systems-level role in gene expression regulation. Understanding their regulation and effects will support the ongoing effort to develop a systems-level understanding of complex immune processes.

However, much work remains. miRNA research has progressed from showing that miRNAs as a whole are important in specific cell types (e.g. Dicer-deficiency in Tregs6-8) to demonstrating that specific miRNAs are important for the immune system. However, there is a number of miRNAs that are important to immune function that have yet to be discovered. Indeed, efforts are ongoing to knockout every possibly immunologically-relevant miRNA in mice to provide a more complete picture of their diverse roles in immunity (Michael T. McManus, personal communication). Once armed with this new knowledge, researchers will next work to pin down specific roles for miRNAs in single cell types. Higher-resolution, genetic studies will be needed, including lineage specific conditional deletions and target mRNA-specific, 3’ UTR mutations.

The field of immunology has historically incorporated the most cutting-edge advances from other fields of biology. Now, with the explosion of miRNA research just over a decade old, immunology is a prime candidate for exploring this complex and powerful mode of gene expression regulation. As more is learned about the role of miRNAs in immunity, more will no doubt be learned about the mechanisms of miRNAs themselves.


Figure 1

The role of specific miRNAs in different immune compartments. The miRNAs depicted are those discussed in this review for which evidence for their role in a given compartment (T cell, B cell, and/or myeloid lineage) has been published. These miRNAs are representative of only those for which there is enough evidence to categorize them with confidence. Further work will no doubt elucidate more miRNAs important to the immune system. (A) The role of specific miRNAs in hematopoietic development and immunity for given cell lineages. (B) The role of specific miRNAs in leukemias and lymphomas for given cell lineages. miRNAs depicted in red have been shown to be tumor suppressors in the given immune compartments, whereas those shown in black have been shown to act as oncomiRs.



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