Mark Ansel, PhD

Assoc Professor in Residence
Microbiology and Immunology
+1 415 476-5368

Naive lymphocytes that encounter their cognate antigens differentiate into a variety of immune effector cells under the influence of cytokines and other inflammatory stimuli. Lymphocyte lineage decisions are critical for the development of protective immunity against a great diversity of pathogens, but improper or exaggerated responses also contribute to the development and pathology of autoimmune diseases, chronic inflammation, allergy, and asthma.
The primary experimental system utilized by the laboratory is the differentiation of helper T cells. Their distinct cellular identities (Th1, Th2, etc.) and associated functions are defined by characteristic gene expression programs. We and many others have documented how these programs are controlled by transcription factors, the cis-regulatory DNA elements to which they bind, and epigenetic modifications that constrain chromatin accessibility at those sites.

More recently, we found that the endogenous RNA interference (RNAi) pathway also regulates helper T cell differentiation, as naive T cells lacking Dicer exhibit rapid, unrestrained differentiation into effector cells. MicroRNAs (miRNA) are the best-characterized class of natural short regulatory RNAs. As they differentiate, T cells reset their miRNA repertoire. This rapid change in miRNA expression may be important to allow T cells to change their gene expression programs and develop effector functions.

The major research goals of our laboratory are: i) to define the molecular mechanisms that control miRNA turnover and determine how this process is accelerated in activated lymphocytes; ii) to characterize the expression and function of noncoding RNAs, including miRNAs, in T cell differentiation, and iii) to extend our work beyond in vitro and mouse models to explore how chromatin remodeling and regulatory RNAs contribute to the pathogenic properties of T cells in human asthma.
MicroRNAs, transcription factors, and epigenetic regulation shape the gene expression programs that determine cell identity and function. The Ansel lab studies how these molecular mechanisms work together to control lymphocyte development, differentiation, and function in immunity.

We use in vitro cell differentiation systems, mouse genetics, disease models, and high dimensional cellular and molecular analyses in human biospecimens to unravel the regulatory networks that underlie immunity and immune pathology, especially allergy and asthma.

Lymphocyte lineage decisions and the deployment of their effector functions are critical for the development of protective immunity against a great diversity of pathogens. However, improper or exaggerated responses underlie the pathogenesis of autoimmune diseases, chronic inflammation, allergy, and asthma. Our primary experimental system is the differentiation of helper T cells, the central coordinators of adaptive immune responses. Upon immune activation, naïve CD4+ T cells can differentiate into several different helper T cell effectors subtypes (e.g. Th1, Th2, Th17, iTreg, Tfh, etc.). These lineages are defined by their characteristic gene expression programs and mediate distinct immune functions. These gene expression programs are controlled by external factors that derive from other cells or the environment, signaling-induced and lineage-specific transcription factors, epigenetic regulation of transcriptional responses, and posttranscriptional mechanisms, including RNA-binding proteins and miRNAs. The depth of our knowledge about the networks that control helper T cells makes them an attractive model for studying basic mechanisms of gene regulation.

Active projects in the laboratory mostly focus on miRNAs. We study how individual miRNA families regulate helper T cell differentiation and immune function, as well as the regulation of the miRNA pathway itself during immune responses. Naive CD4+ T cells that cannot produce any miRNAs exhibit reduced cell division and survival in response to immune stimuli. Surprisingly, they also undergo rapid unrestrained differentiation into effector cells. We have developed a screening technology that allows us to rapidly determine which specific miRNAs regulate each of these T cell behaviors, and a high throughput nanoscaled pipeline for determining miRNA expression patterns in small clinical samples (such as sorted T cell subsets from the airways of human asthmatic subjects, serum, sputum, and other sources of extracellular miRNAs, etc.). In addition, we discovered that T cells rapidly reset their miRNA repertoire upon activation. This process that involves ubiquitination and degradation of Argonaute proteins, but the signaling mechanisms and the fate of associated miRNAs remains unknown. This rapid change in miRNA expression may be important to allow T cells to change their gene expression programs and develop effector functions.

The major research goals of our laboratory are:

1) To define the molecular mechanisms that control miRNA homeostasis in lymphocytes, and determine how the miRNA repertoire is so dramatically remodeled during T cell activation.

2) To characterize the function of individual miRNAs that regulate T cell differentiation and immune effector functions.

3) To determine how the expression and function of miRNAs contribute to the pathogenic properties of T cells in human asthma.

Publications: 

A Distinct Inhibitory Function for miR-18a in Th17 Cell Differentiation.

Journal of immunology (Baltimore, Md. : 1950)

Montoya MM, Maul J, Singh PB, Pua HH, Dahlström F, Wu N, Huang X, Ansel KM, Baumjohann D

Small RNA Transfection in Primary Human Th17 Cells by Next Generation Electroporation.

Journal of visualized experiments : JoVE

Montoya MM, Ansel KM

Alternative splicing of interleukin-33 and type 2 inflammation in asthma.

Proceedings of the National Academy of Sciences of the United States of America

Gordon ED, Simpson LJ, Rios CL, Ringel L, Lachowicz-Scroggins ME, Peters MC, Wesolowska-Andersen A, Gonzalez JR, MacLeod HJ, Christian LS, Yuan S, Barry L, Woodruff PG, Ansel KM, Nocka K, Seibold MA, Fahy JV

IFN-?-Producing T-Helper 17.1 Cells Are Increased in Sarcoidosis and Are More Prevalent than T-Helper Type 1 Cells.

American journal of respiratory and critical care medicine

Ramstein J, Broos CE, Simpson LJ, Ansel KM, Sun SA, Ho ME, Woodruff PG, Bhakta NR, Christian L, Nguyen CP, Antalek BJ, Benn BS, Hendriks RW, van den Blink B, Kool M, Koth LL

MicroRNAs 24 and 27 Suppress Allergic Inflammation and Target a Network of Regulators of T Helper 2 Cell-Associated Cytokine Production.

Immunity

Pua HH, Steiner DF, Patel S, Gonzalez JR, Ortiz-Carpena JF, Kageyama R, Chiou NT, Gallman A, de Kouchkovsky D, Jeker LT, McManus MT, Erle DJ, Ansel KM

Biogenesis, delivery, and function of extracellular RNA.

Journal of extracellular vesicles

Patton JG, Franklin JL, Weaver AM, Vickers K, Zhang B, Coffey RJ, Ansel KM, Blelloch R, Goga A, Huang B, L'Etoille N, Raffai RL, Lai CP, Krichevsky AM, Mateescu B, Greiner VJ, Hunter C, Voinnet O, McManus MT

MicroRNA regulation of allergic inflammation and asthma.

Current opinion in immunology

Pua HH, Ansel KM

mir-181a-1/b-1 Modulates Tolerance through Opposing Activities in Selection and Peripheral T Cell Function.

Journal of immunology (Baltimore, Md. : 1950)

Schaffert SA, Loh C, Wang S, Arnold CP, Axtell RC, Newell EW, Nolan G, Ansel KM, Davis MM, Steinman L, Chen CZ

MicroRNA regulation of lymphocyte tolerance and autoimmunity.

The Journal of clinical investigation

Simpson LJ, Ansel KM

Self-enforcing feedback activation between BCL6 and pre-B cell receptor signaling defines a distinct subtype of acute lymphoblastic leukemia.

Cancer cell

Geng H, Hurtz C, Lenz KB, Chen Z, Baumjohann D, Thompson S, Goloviznina NA, Chen WY, Huan J, LaTocha D, Ballabio E, Xiao G, Lee JW, Deucher A, Qi Z, Park E, Huang C, Nahar R, Kweon SM, Shojaee S, Chan LN, Yu J, Kornblau SM, Bijl JJ, Ye BH, Ansel KM, Paietta E, Melnick A, Hunger SP, Kurre P, Tyner JW, Loh ML, Roeder RG, Druker BJ, Burger JA, Milne TA, Chang BH, Müschen M

Induced miR-99a expression represses Mtor cooperatively with miR-150 to promote regulatory T-cell differentiation.

The EMBO journal

Warth SC, Hoefig KP, Hiekel A, Schallenberg S, Jovanovic K, Klein L, Kretschmer K, Ansel KM, Heissmeyer V

The transcription factor NFAT promotes exhaustion of activated CD8? T cells.

Immunity

Martinez GJ, Pereira RM, Äijö T, Kim EY, Marangoni F, Pipkin ME, Togher S, Heissmeyer V, Zhang YC, Crotty S, Lamperti ED, Ansel KM, Mempel TR, Lähdesmäki H, Hogan PG, Rao A

Tracking early T follicular helper cell differentiation in vivo.

Methods in molecular biology (Clifton, N.J.)

Baumjohann D, Ansel KM

Editorial overview: Allergy and hypersensitivity.

Current opinion in immunology

Sperling AI, Ansel KM

A microRNA upregulated in asthma airway T cells promotes TH2 cytokine production.

Nature immunology

Simpson LJ, Patel S, Bhakta NR, Choy DF, Brightbill HD, Ren X, Wang Y, Pua HH, Baumjohann D, Montoya MM, Panduro M, Remedios KA, Huang X, Fahy JV, Arron JR, Woodruff PG, Ansel KM

Epigenomic analysis of primary human T cells reveals enhancers associated with TH2 memory cell differentiation and asthma susceptibility.

Nature immunology

Seumois G, Chavez L, Gerasimova A, Lienhard M, Omran N, Kalinke L, Vedanayagam M, Ganesan AP, Chawla A, Djukanovic R, Ansel KM, Peters B, Rao A, Vijayanand P

Eri1: a conserved enzyme at the crossroads of multiple RNA-processing pathways.

Trends in genetics : TIG

Thomas MF, L'Etoile ND, Ansel KM

MicroRNA regulation of the germinal center response.

Current opinion in immunology

Baumjohann D, Ansel KM

Comparative transcriptional and functional profiling defines conserved programs of intestinal DC differentiation in humans and mice.

Nature immunology

Watchmaker PB, Lahl K, Lee M, Baumjohann D, Morton J, Kim SJ, Zeng R, Dent A, Ansel KM, Diamond B, Hadeiba H, Butcher EC

The microRNA cluster miR-17~92 promotes TFH cell differentiation and represses subset-inappropriate gene expression.

Nature immunology

Baumjohann D, Kageyama R, Clingan JM, Morar MM, Patel S, de Kouchkovsky D, Bannard O, Bluestone JA, Matloubian M, Ansel KM, Jeker LT

RNA regulation of the immune system.

Immunological reviews

Ansel KM

Regulation of miRNA biogenesis and turnover in the immune system.

Immunological reviews

Bronevetsky Y, Ansel KM

Persistent antigen and germinal center B cells sustain T follicular helper cell responses and phenotype.

Immunity

Baumjohann D, Preite S, Reboldi A, Ronchi F, Ansel KM, Lanzavecchia A, Sallusto F

T cell activation induces proteasomal degradation of Argonaute and rapid remodeling of the microRNA repertoire.

The Journal of experimental medicine

Bronevetsky Y, Villarino AV, Eisley CJ, Barbeau R, Barczak AJ, Heinz GA, Kremmer E, Heissmeyer V, McManus MT, Erle DJ, Rao A, Ansel KM

Eri1 degrades the stem-loop of oligouridylated histone mRNAs to induce replication-dependent decay.

Nature structural & molecular biology

Hoefig KP, Rath N, Heinz GA, Wolf C, Dameris J, Schepers A, Kremmer E, Ansel KM, Heissmeyer V

An integrated nano-scale approach to profile miRNAs in limited clinical samples.

American journal of clinical and experimental immunology

Seumois G, Vijayanand P, Eisley CJ, Omran N, Kalinke L, North M, Ganesan AP, Simpson LJ, Hunkapiller N, Moltzahn F, Woodruff PG, Fahy JV, Erle DJ, Djukanovic R, Blelloch R, Ansel KM

Airway epithelial miRNA expression is altered in asthma.

American journal of respiratory and critical care medicine

Solberg OD, Ostrin EJ, Love MI, Peng JC, Bhakta NR, Hou L, Nguyen C, Solon M, Nguyen C, Barczak AJ, Zlock LT, Blagev DP, Finkbeiner WE, Ansel KM, Arron JR, Erle DJ, Woodruff PG

Eri1 regulates microRNA homeostasis and mouse lymphocyte development and antiviral function.

Blood

Thomas MF, Abdul-Wajid S, Panduro M, Babiarz JE, Rajaram M, Woodruff P, Lanier LL, Heissmeyer V, Ansel KM

Interleukin-4 production by follicular helper T cells requires the conserved Il4 enhancer hypersensitivity site V.

Immunity

Vijayanand P, Seumois G, Simpson LJ, Abdul-Wajid S, Baumjohann D, Panduro M, Huang X, Interlandi J, Djuretic IM, Brown DR, Sharpe AH, Rao A, Ansel KM

MicroRNA-29 regulates T-box transcription factors and interferon-? production in helper T cells.

Immunity

Steiner DF, Thomas MF, Hu JK, Yang Z, Babiarz JE, Allen CD, Matloubian M, Blelloch R, Ansel KM

Cutting Edge: Distinct waves of BCL6 expression during T follicular helper cell development.

Journal of immunology (Baltimore, Md. : 1950)

Baumjohann D, Okada T, Ansel KM

Induction and maintenance of IL-4 expression are regulated differently by the 3' enhancer in CD4 T cells.

Journal of immunology (Baltimore, Md. : 1950)

Sofi MH, Qiao Y, Ansel KM, Kubo M, Chang CH

Six RNA viruses and forty-one hosts: viral small RNAs and modulation of small RNA repertoires in vertebrate and invertebrate systems.

PLoS pathogens

Parameswaran P, Sklan E, Wilkins C, Burgon T, Samuel MA, Lu R, Ansel KM, Heissmeyer V, Einav S, Jackson W, Doukas T, Paranjape S, Polacek C, dos Santos FB, Jalili R, Babrzadeh F, Gharizadeh B, Grimm D, Kay M, Koike S, Sarnow P, Ronaghi M, Ding SW, Harris E, Chow M, Diamond MS, Kirkegaard K, Glenn JS, Fire AZ

Construction of small RNA cDNA libraries for deep sequencing.

Methods in molecular biology (Clifton, N.J.)

Thomas MF, Ansel KM

Mouse Eri1 interacts with the ribosome and catalyzes 5.8S rRNA processing.

Nature structural & molecular biology

Ansel KM, Pastor WA, Rath N, Lapan AD, Glasmacher E, Wolf C, Smith LC, Papadopoulou N, Lamperti ED, Tahiliani M, Ellwart JW, Shi Y, Kremmer E, Rao A, Heissmeyer V

Role of CXCR5 and CCR7 in follicular Th cell positioning and appearance of a programmed cell death gene-1high germinal center-associated subpopulation.

Journal of immunology (Baltimore, Md. : 1950)

Haynes NM, Allen CD, Lesley R, Ansel KM, Killeen N, Cyster JG

The NFAT1 transcription factor is a repressor of cyclin A2 gene expression.

Cell cycle (Georgetown, Tex.)

Carvalho LD, Teixeira LK, Carrossini N, Caldeira AT, Ansel KM, Rao A, Viola JP

Regulation of the germinal center response by microRNA-155.

Science (New York, N.Y.)

Thai TH, Calado DP, Casola S, Ansel KM, Xiao C, Xue Y, Murphy A, Frendewey D, Valenzuela D, Kutok JL, Schmidt-Supprian M, Rajewsky N, Yancopoulos G, Rao A, Rajewsky K

Transcription factors T-bet and Runx3 cooperate to activate Ifng and silence Il4 in T helper type 1 cells.

Nature immunology

Djuretic IM, Levanon D, Negreanu V, Groner Y, Rao A, Ansel KM

Regulation of Th2 differentiation and Il4 locus accessibility.

Annual review of immunology

Ansel KM, Djuretic I, Tanasa B, Rao A

MicroRNA profiling of the murine hematopoietic system.

Genome biology

Monticelli S, Ansel KM, Xiao C, Socci ND, Krichevsky AM, Thai TH, Rajewsky N, Marks DS, Sander C, Rajewsky K, Rao A, Kosik KS

Aberrant T cell differentiation in the absence of Dicer.

The Journal of experimental medicine

Muljo SA, Ansel KM, Kanellopoulou C, Livingston DM, Rao A, Rajewsky K

A plague of autoantibodies.

Nature immunology

Heissmeyer V, Ansel KM, Rao A

Intrinsic lymphotoxin-beta receptor requirement for homeostasis of lymphoid tissue dendritic cells.

Immunity

Kabashima K, Banks TA, Ansel KM, Lu TT, Ware CF, Cyster JG

Deletion of a conserved Il4 silencer impairs T helper type 1-mediated immunity.

Nature immunology

Ansel KM, Greenwald RJ, Agarwal S, Bassing CH, Monticelli S, Interlandi J, Djuretic IM, Lee DU, Sharpe AH, Alt FW, Rao A

Germinal center dark and light zone organization is mediated by CXCR4 and CXCR5.

Nature immunology

Allen CD, Ansel KM, Low C, Lesley R, Tamamura H, Fujii N, Cyster JG

An epigenetic view of helper T cell differentiation.

Nature immunology

Ansel KM, Lee DU, Rao A

Overlapping roles of CXCL13, interleukin 7 receptor alpha, and CCR7 ligands in lymph node development.

The Journal of experimental medicine

Luther SA, Ansel KM, Cyster JG

Traffic patterns of B cells and plasma cells.

Advances in experimental medicine and biology

Cyster JG, Ansel KM, Ngo VN, Hargreaves DC, Lu TT

Chemokines in lymphopoiesis and lymphoid organ development.

Current opinion in immunology

Ansel KM, Cyster JG

Follicular stromal cells and lymphocyte homing to follicles.

Immunological reviews

Cyster JG, Ansel KM, Reif K, Ekland EH, Hyman PL, Tang HL, Luther SA, Ngo VN

A chemokine-driven positive feedback loop organizes lymphoid follicles.

Nature

Ansel KM, Ngo VN, Hyman PL, Luther SA, Förster R, Sedgwick JD, Browning JL, Lipp M, Cyster JG

In vivo-activated CD4 T cells upregulate CXC chemokine receptor 5 and reprogram their response to lymphoid chemokines.

The Journal of experimental medicine

Ansel KM, McHeyzer-Williams LJ, Ngo VN, McHeyzer-Williams MG, Cyster JG

Chemokines and B-cell homing to follicles.

Current topics in microbiology and immunology

Cyster JG, Ngo VN, Ekland EH, Gunn MD, Sedgwick JD, Ansel KM

A B-cell-homing chemokine made in lymphoid follicles activates Burkitt's lymphoma receptor-1.

Nature

Gunn MD, Ngo VN, Ansel KM, Ekland EH, Cyster JG, Williams LT