Dan R. Littman, MD, PhD
Helen and Martin Kimmel Professor of Molecular Immunology
Investigator, Howard Hughes Medical Institute
M.D., Ph.D., 1980 Washington University in St. Louis.
Immune System Development, T Cell Lineage Choice, Intestinal Epithelial Stem Cell Responses to Microbiota
T cell differentiation, Lineage Choice, Epigenetics, Transcription Factor Networks, Microbiota, Intestinal epithelial stem cells
Skirball Institute of Biomolecular Medicine
New York University School of Medicine
540 First Ave., 2nd floor
New York, NY 10016
Office Tel: (212) 263-7579
Lab Tel: (212) 263-6921
Differentiation from stem cells into mature cells of any tissue requires the concerted efforts of transcription factors, which activate necessary gene expression programs, and epigenetic mechanisms, which lock in these programs. To understand these basic mechanisms, we study the signaling pathways and transcriptional networks involved in development of T lymphocytes and in their responses to inflammatory microbial signals.
The majority of mature T lymphocytes fall into one of two functional categories: helper cells, which react with peptides complexed to major histocompatibility complex (MHC) class II molecules on antigen-presenting cells, and cytotoxic cells, which recognize peptides bound to MHC class I molecules. These cells are distinguished on the basis of surface expression of the CD4 or CD8 coreceptors, which are coexpressed on immature double-positive (DP) thymocytes but are singly expressed upon maturation on thymocytes with T cell antigen receptors (TCRs) specific for class II and class I, respectively.
As commitment to the cytotoxic or helper lineage is coupled to the transcriptional shutoff of cd4 or cd8, we have studied the transcriptional regulation of the coreceptor genes to understand the mechanism of lineage specification. We identified a region within the Cd4 gene that is required to initiate, but not maintain the silencing of cd4 expression in the cytotoxic T cell lineage. Further, we have shown that an enhancer necessary to initiate cd4 expression in DP thymocytes, establishes a heritable state of active gene expression that is maintained in mature T helper cells even after the enhancer’s deletion. Thus, Cd4 is regulated by heritable ON and OFF epigenetic mechanisms. Work to identify trans-acting factors involved in the initiation and maintenance of these heritable states has yielded the Runx 1 and 3 transcription factors, which are crucial for the differentiation of helper and cytotoxic T cells, respectively. In addition, we have shown that the transcription factor ThPOK, which is required for helper T cell differentiation, represses Runx3 and thus, cytotoxic T cell fate. We continue to seek to identify the transacting factors that participate in the transcriptional network critical to coreceptor expression and lineage choice. Currently we are especially interested in the role of DNA methylation and noncoding RNAs in lineage specification and cd4 silencing.
Naïve helper T cells can differentiate into different flavors of effector helper cells, which are defined by cytokine secretion patterns and are critical for defense against certain types of infections. A proinflammatory subset, called Th17 cells, expresses the cytokines interleukin-17 (IL-17) and IL-22, and is especially important for immunity to extracellular pathogens, particularly at mucosal sites. In addition, aberrant activation of these cells is thought to be involved in a wide range of autoimmune diseases, including multiple sclerosis, arthritis and inflammatory bowel disease. Our work has shown that the transcription factor RORgt is a central regulator of Th17 cells: forced expression of RORgt induces IL-17, while its deletion largely abrogates IL-17 expression and pathogenesis associated with mouse models of multiple sclerosis. We have shown that signals from TGF-b, IL-6, IL-21 and IL-23 synergize to induce RORgt expression and program Th17 differentiation. Further we have identified a commensal gut microbe, Segmented Filamentous Bacteria, whose presence induces Th17 cell differentiation.
We are now pursuing additional studies to characterize transcriptional and post-transcriptional regulatory networks involved in Th17 cell differentiation. In addition to RORγt, there are at least eight other transcription factors known to be required for induction of IL-17 or IL-22. By combining expression profiling in T cells that lack any one of these factors with genome-wide chromatin immunoprecipitation (RNA-seq and ChIP-seq), we have identified numerous new nodes in the Th17 cell transcriptional network. Ongoing studies using genetic and biochemical approaches will elucidate how transcription factor networks program cellular identity, and may help identify novel targets for modulation of inflammatory lymphocyte function.
Finally, we also investigate how the composition of the commensal microbiota influences host defense against pathogens, and how the human immunodeficiency virus (HIV) interacts with host cells to subvert normal immune defenses to its advantage. In this regard, we are investigating how microbiota-derived signals influence the dynamics of intestinal epithelial cell renewal and, in particular, the response of intestinal epithelial cells and diverse progenitor cells to lymphocyte-derived cytokines.
- Diehl, Gretchen E; Longman, Randy S; Zhang, Jing-Xin; Breart, Beatrice; Galan, Carolina; Cuesta, Adolfo; Schwab, Susan R; LITTMAN, DAN R. Microbiota restricts trafficking of bacteria to mesenteric lymph nodes by CX3CR1hi cells. Nature 2013 Feb;494(7435):116-120. PMID: 23334413
- Kim, Sangwon V; Xiang, Wenkai V; Kwak, Changsoo; Yang, Yi; Lin, Xiyao W; Ota, Mitsuhiko; Sarpel, Umut; Rifkin, Daniel B; Xu, Ruliang; Littman, Dan R. GPR15-Mediated Homing Controls Immune Homeostasis in the Large Intestine Mucosa. Science 2013 Jun;340(6139):1456-1459. PMID: 23661644
- Ciofani, Maria; Madar, Aviv; Galan, Carolina; Sellars, Maclean; Mace, Kieran; Pauli, Florencia; Agarwal, Ashish; Huang, Wendy; Parkurst, Christopher N; Muratet, Michael; Newberry, Kim M; Meadows, Sarah; Greenfield, Alex; Yang, Yi; Jain, Preti; Kirigin, Francis K; Birchmeier, Carmen; Wagner, Erwin F; Murphy, Kenneth M; Myers, Richard M; Bonneau, Richard; Littman, Dan R. A validated regulatory network for th17 cell specification. Cell 2012 Oct;151(2):289-303. PMID: 23021777
- Egawa, Takeshi; Littman, Dan R. Transcription factor AP4 modulates reversible and epigenetic silencing of the Cd4 gene. Proceedings of the National Academy of Sciences of the United States of America 2011 Sep 6;108(36):14873-14878. PMID: 21873191
- Huh, Jun R; Leung, Monica W L; Huang, Pengxiang; Ryan, Daniel A; Krout, Michael R; Malapaka, Raghu R V; Chow, Jonathan; Manel, Nicolas; Ciofani, Maria; Kim, Sangwon V; Cuesta, Adolfo; Santori, Fabio R; Lafaille, Juan J; Xu, H Eric; Gin, David Y; Rastinejad, Fraydoon; Littman, Dan R. Digoxin and its derivatives suppress TH17 cell differentiation by antagonizing RORgammat activity. Nature 2011 Apr 28;472(7344):486-490. PMID: 21441909
- Manel, Nicolas; LITTMAN, DAN R. Hiding in Plain Sight: How HIV Evades Innate Immune Responses. Cell 2011 OCT 14 ;147(2):271-274. PMID: 22000008
- Chong, M.M., N. Simpson, M. Ciofani, G. Chen, A. Collins and D.R. Littman, (2010) Epigenetic propagation of CD4 expression is established by the Cd4 proximal enhancer in helper T cells. Genes Dev, 24(7): p. 659-69. PMID: 20360383
- Chong, M.M., G. Zhang, S. Cheloufi, T.A. Neubert, G.J. Hannon and D.R. Littman (2010) Canonical and alternate functions of the microRNA biogenesis machinery. Genes Dev. 24(17): p. 1951-60. PMID: 20713509
- Manel, N., B. Hogstad, Y. Wang, D.E. Levy, D. Unutmaz and D.R. Littman. (2010) A cryptic sensor for HIV-1 activates antiviral innate immunity in dendritic cells. Nature. 467(7312): p. 214-7. PMID: 20829794
- Ivanov, II, K. Atarashi, N. Manel, E.L. Brodie, T. Shima, U. Karaoz, D. Wei, K.C. Goldfarb, C.A. Santee, S.V. Lynch, T. Tanoue, A. Imaoka, K. Itoh, K. Takeda, Y. Umesaki, K. Honda and D.R. Littman. (2009) Induction of intestinal Th17 cells by segmented filamentous bacteria. Cell. 139(3): p. 485-98. PMID: 19836068
- Chong, M.M., J.P. Rasmussen, A.Y. Rudensky and D.R. Littman. (2008) The RNAseIII enzyme Drosha is critical in T cells for preventing lethal inflammatory disease. J Exp Med. 205(9): p. 2005-17. PMID: 18725527
- Egawa, T. and D.R. Littman. (2008) ThPOK acts late in specification of the helper T cell lineage and suppresses Runx-mediated commitment to the cytotoxic T cell lineage. Nat Immunol. 9(10): p. 1131-9. PMID: 18776905
- Ivanov, II, L. Frutos Rde, N. Manel, K. Yoshinaga, D.B. Rifkin, R.B. Sartor, B.B. Finlay and D.R. Littman. (2008) Specific microbiota direct the differentiation of IL-17-producing T-helper cells in the mucosa of the small intestine. Cell Host Microbe. 4(4): p. 337-49. PMID: 18854238
- Manel, N., D. Unutmaz and D.R. Littman. (2008) The differentiation of human T(H)-17 cells requires transforming growth factor-beta and induction of the nuclear receptor RORgammat. Nat Immunol. 9(6): p. 641-9. PMID: 18454151
- Zhou, L., J.E. Lopes, M.M. Chong, Ivanov, II, R. Min, G.D. Victora, Y. Shen, J. Du, Y.P. Rubtsov, A.Y. Rudensky, S.F. Ziegler and D.R. Littman. (2008) TGF-beta-induced Foxp3 inhibits T(H)17 cell differentiation by antagonizing RORgammat function. Nature. 453(7192): p. 236-40. PMID: 18368049
- Egawa, T., R.E. Tillman, Y. Naoe, I. Taniuchi and D.R. Littman. (2007) The role of the Runx transcription factors in thymocyte differentiation and in homeostasis of naive T cells. J Exp Med. 204(8): p. 1945-57. PMID: 17646406
- Zhou, L., Ivanov, II, R. Spolski, R. Min, K. Shenderov, T. Egawa, D.E. Levy, W.J. Leonard and D.R. Littman. (2007) IL-6 programs T(H)-17 cell differentiation by promoting sequential engagement of the IL-21 and IL-23 pathways. Nat Immunol. 8(9): p. 967-74. PMID: 17581537