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.
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
Lab Website: http://saturn.med.nyu.edu/research/mp/littmanlab/index.html
Research Theme(s): Immune System Development, Lineage Choice
Keywords: T cell differentiation, Lineage Choice, Epigenetics, Transcription Factor Networks
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 aim to determine the targets for each transcription factor and characterize the transcriptional network for Th17 cells. These studies 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.
- Role of the commensal microbiota in normal and pathogenic host immune responses. Littman DR, Pamer EG. Cell Host Microbe. 2011 Oct 4;10(4):311-23. PMID: 22018232
- Hiding in Plain Sight: How HIV Evades Innate Immune Responses. Manel N, Littman DR. Cell. 2011 Oct 14;147(2):271-4. PMID: 22000008
- The Epigenetic Landscape of Lineage Choice: Lessons From the Heritability of Cd4 and Cd8 Expression. Gialitakis M, Sellars M, Littman DR. Curr Top Microbiol Immunol. 2011 Oct 12. [Epub ahead of print] PMID: 21989924
- The genome of th17 cell-inducing segmented filamentous bacteria reveals extensive auxotrophy and adaptations to the intestinal environment. Sczesnak A, Segata N, Qin X, Gevers D, Petrosino JF, Huttenhower C, Littman DR, Ivanov II. Cell Host Microbe. 2011 Sep 15;10(3):260-72. doi: 10.1016/j.chom.2011.08.005. PMID: 21925113
- Transcription factor AP4 modulates reversible and epigenetic silencing of the Cd4 gene. Egawa T, Littman DR. Proc Natl Acad Sci U S A. 2011 Sep 6;108(36):14873-8. Epub 2011 Aug 22. PMID: 21873191
- Regulatory T cells suppress development of colitis, blocking differentiation of T-helper 17 into alternative T-helper 1 cells. Sujino T, Kanai T, Ono Y, Mikami Y, Hayashi A, Doi T, Matsuoka K, Hisamatsu T, Takaishi H, Ogata H, Yoshimura A, Littman DR, Hibi T. Gastroenterology. 2011 Sep;141(3):1014-23. Epub 2011 Jun 7. PMID: 21699791
- The inducible deletion of Drosha and microRNAs in mature podocytes results in a collapsing glomerulopathy. Zhdanova O, Srivastava S, Di L, Li Z, Tchelebi L, Dworkin S, Johnstone DB, Zavadil J, Chong MM, Littman DR, Holzman LB, Barisoni L, Skolnik EY. Kidney Int. 2011 Oct;80(7):719-30. doi: 10.1038/ki.2011.122. Epub 2011 May 4. PMID: 21544061
- Digoxin and its derivatives suppress TH17 cell differentiation by antagonizing RORγt activity. Huh JR, Leung MW, Huang P, Ryan DA, Krout MR, Malapaka RR, Chow J, Manel N, Ciofani M, Kim SV, Cuesta A, Santori FR, Lafaille JJ, Xu HE, Gin DY, Rastinejad F, Littman DR. Nature. 2011 Apr 28;472(7344):486-90. Epub 2011 Mar 27. PMID: 21441909
- RUNX transcription factor-mediated association of Cd4 and Cd8 enables coordinate gene regulation. Collins A, Hewitt SL, Chaumeil J, Sellars M, Micsinai M, Allinne J, Parisi F, Nora EP, Bolland DJ, Corcoran AE, Kluger Y, Bosselut R, Ellmeier W, Chong MM, Littman DR, Skok JA. Immunity. 2011 Mar 25;34(3):303-14. PMID: 21435585
- CXCR7 influences leukocyte entry into the CNS parenchyma by controlling abluminal CXCL12 abundance during autoimmunity. Cruz-Orengo L, Holman DW, Dorsey D, Zhou L, Zhang P, Wright M, McCandless EE, Patel JR, Luker GD, Littman DR, Russell JH, Klein RS. J Exp Med. 2011 Feb 14;208(2):327-39. Epub 2011 Feb 7. PMID: 21300915
- DICER1 deficit induces Alu RNA toxicity in age-related macular degeneration. Kaneko H, Dridi S, Tarallo V, Gelfand BD, Fowler BJ, Cho WG, Kleinman ME, Ponicsan SL, Hauswirth WW, Chiodo VA, Karikó K, Yoo JW, Lee DK, Hadziahmetovic M, Song Y, Misra S, Chaudhuri G, Buaas FW, Braun RE, Hinton DR, Zhang Q, Grossniklaus HE, Provis JM, Madigan MC, Milam AH, Justice NL, Albuquerque RJ, Blandford AD, Bogdanovich S, Hirano Y, Witta J, Fuchs E, Littman DR, Ambati BK, Rudin CM, Chong MM, Provost P, Kugel JF, Goodrich JA, Dunaief JL, Baffi JZ, Ambati J. Nature. 2011 Mar 17;471(7338):325-30. Epub 2011 Feb 6. PMID: 21297615
- Modulation of immune homeostasis by commensal bacteria. Ivanov II, Littman DR. Curr Opin Microbiol. 2011 Feb;14(1):106-14. Epub 2011 Jan 5. Review. PMID: 21215684
- Characterization of interleukin-17-producing regulatory T cells in inflamed intestinal mucosa from patients with inflammatory bowel diseases. Hovhannisyan Z, Treatman J, Littman DR, Mayer L. Gastroenterology. 2011 Mar;140(3):957-65. Epub 2010 Dec 11. PMID: 21147109
- Epigenetic propagation of CD4 expression is established by the Cd4 proximal enhancer in helper T cells. Chong, M.M., N. Simpson, M. Ciofani, G. Chen, A. Collins and D.R. Littman, Genes Dev, 2010. 24(7): p. 659-69.8. PMID: 20360383
- Canonical and alternate functions of the microRNA biogenesis machinery. Chong, M.M., G. Zhang, S. Cheloufi, T.A. Neubert, G.J. Hannon and D.R. Littman, Genes Dev, 2010. 24(17): p. 1951-60.7. PMID: 20713509
- A cryptic sensor for HIV-1 activates antiviral innate immunity in dendritic cells .Manel, N., B. Hogstad, Y. Wang, D.E. Levy, D. Unutmaz and D.R. Littman, Nature, 2010. 467(7312): p. 214-7.452. PMID: 20829794
- Induction of intestinal Th17 cells by segmented filamentous bacteria. 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, Cell, 2009. 139(3): p. 485-98.458. PMID: 19836068
- The RNAseIII enzyme Drosha is critical in T cells for preventing lethal inflammatory disease. Chong, M.M., J.P. Rasmussen, A.Y. Rudensky and D.R. Littman, J Exp Med, 2008. 205(9): p. 2005-17.466. PMID: 18725527
- ThPOK acts late in specification of the helper T cell lineage and suppresses Runx-mediated commitment to the cytotoxic T cell lineage. Egawa, T. and D.R. Littman, Nat Immunol, 2008. 9(10): p. 1131-9.207. PMID: 18776905
- Specific microbiota direct the differentiation of IL-17-producing T-helper cells in the mucosa of the small intestine. Ivanov, II, L. Frutos Rde, N. Manel, K. Yoshinaga, D.B. Rifkin, R.B. Sartor, B.B. Finlay and D.R. Littman, Cell Host Microbe, 2008. 4(4): p. 337-49.464. PMID: 18854238
- The differentiation of human T(H)-17 cells requires transforming growth factor-beta and induction of the nuclear receptor RORgammat. Manel, N., D. Unutmaz and D.R. Littman, Nat Immunol, 2008. 9(6): p. 641-9.468. PMID:18454151
- TGF-beta-induced Foxp3 inhibits T(H)17 cell differentiation by antagonizing RORgammat function. 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, Nature, 2008. 453(7192): p. 236-40.3. PMID: 18368049
- The role of the Runx transcription factors in thymocyte differentiation and in homeostasis of naive T cells. Egawa, T., R.E. Tillman, Y. Naoe, I. Taniuchi and D.R. Littman, J Exp Med, 2007. 204(8): p. 1945-57.245. PMID: 17646406
- IL-6 programs T(H)-17 cell differentiation by promoting sequential engagement of the IL-21 and IL-23 pathways. Zhou, L., Ivanov, II, R. Spolski, R. Min, K. Shenderov, T. Egawa, D.E. Levy, W.J. Leonard and D.R. Littman, Nat Immunol, 2007. 8(9): p. 967-74.5. PMID: 17581537
- Thymic origin of intestinal alphabeta T cells revealed by fate mapping of RORgammat+ cells. Eberl, G. and D.R. Littman, Science, 2004. 305(5681): p. 248-51.491. PMID: 15247480
- Differential requirements for Runx proteins in CD4 repression and epigenetic silencing during T lymphocyte development. Taniuchi, I., M. Osato, T. Egawa, M.J. Sunshine, S.C. Bae, T. Komori, Y. Ito and D.R. Littman, Cell, 2002. 111(5): p. 621-33.29. PMID: 12464175
- Evidence for distinct CD4 silencer functions at different stages of thymocyte differentiation. Taniuchi, I., M.J. Sunshine, R. Festenstein and D.R. Littman, Mol Cell, 2002. 10(5): p. 1083-96.30. PMID:12453416
- Epigenetic silencing of CD4 in T cells committed to the cytotoxic lineage. Zou, Y.R., M.J. Sunshine, I. Taniuchi, F. Hatam, N. Killeen and D.R. Littman, Nat Genet, 2001. 29(3): p. 332-6.28. PMID: 11687799