Dan R. Littman

Helen L. and Martin S. Kimmel Professor of Molecular Immunology; Professor, Skirball Institute of Biomolecular Medicine, Molecular Pathogenesis. Departments of Pathology and Microbiology. HHMI Investigator.

Ph.D., 1980 Washington University, St. Louis

Lab Website: http://saturn.med.nyu.edu/research/mp/littmanlab

Keywords:

Contact Information: 

Skirball Institute of Biomolecular Medicine
540 First Avenue 2nd floor, Lab 17
New York, N.Y. 10016
Office Tel: (212) 263-7579
Lab Tel: (212) 263-6957
Fax: (212) 263-5711
E-mail: dan.littman@med.nyu.edu

Administrative Contact:

Jeff Blenker
Tel: (212) 263-7520
Email: jeff.blenker@med.nyu.edu


T Lymphocyte Development and Retroviral Pathogenesis

Our laboratory studies the molecular mechanisms involved in the specification of distinct T lymphocyte lineages during development in the thymus and in response to microbial challenge in peripheral tissues. Elucidation of these mechanisms will help us to understand how normal protective immune responses differ from pathogenic ones that result in inflammation and autoimmune disease. Our studies on thymocytes are focused on how they are specified to differentiate towards either the helper or cytotoxic lineages. We are characterizing the transcription factors involved in lineage specification and in regulation of CD4 and CD8 gene expression, with emphasis on the roles of Runx and ThPOK and the mechanisms for establishing epigenetic programs in maturing T cells.

Our studies on peripheral T cells have led to the indentification of another transcription factor, the nuclear receptor ROR-gt, that is required for the differentiation of highly inflammatory Th17 cells. We are investigating how commensal microbiota, cytokine signaling and interactions between transcription factors influence differentiation of T helper cells towards the Th17 versus the anti-inflammatory regulatory T cell lineages.

We are also examining the functions of different chemokine receptors in migration of T cells and myeloid lineage cells to sites of inflammation and in the regulation of T cell homeostasis, particularly at mucosal sites where commensal microorganisms must be distinguished from potentially harmful pathogenic ones. A related interest is in the characterization of RORgt-expressing lymphoid lineage cells that induce differentiation of secondary lymphoid organs in the fetus and of microbiota-dependent intestinal tertiary lymphoid follicles in the adult.

A distinct area of interest of the laboratory is in elucidating the mechanisms by which the Human Immunodeficiency Virus is transmitted and damages the immune system. HIV fuses to target cells after binding to CD4 and various chemokine receptors. Infection of T cells is enhanced if HIV is first internalized by dendritic cells into a specialized endocytic compartment and then presented to the target cell. We are employing genetic and cell biological approaches to study the mechanism for enhancement of viral entry by dendritic cells. We are also developing mouse models to study the potential role of dendritic cells in vivo in HIV infection and pathogenesis. Other studies are aimed at identifying novel host cell factors required for HIV to complete its replication cycle in human cells. The function of several host factors is species-restricted (e.g. CD4 and chemokine receptors), and their absence from murine cells results in poor HIV replication. Identification of additional factors may facilitate development of a murine model for HIV disease, which can then be used to study mechanisms of pathogenesis as well as to develop new therapies and vaccines.

Selected Publications:

A Validated Regulatory Network for Th17 Cell Specification. Ciofani M, Madar A, Galan C, Sellars M, Mace K, Pauli F, Agarwal A, Huang W, Parkurst CN, Muratet M, Newberry KM, Meadows S, Greenfield A, Yang Y, Jain P, Kirigin FK, Birchmeier C, Wagner EF, Murphy KM, Myers RM, Bonneau R, Littman DR. Cell. 2012 Sep 22. pii: S0092-8674(12)01123-3. doi: 10.1016/j.cell.2012.09.016. PMID: 23021777

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

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

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. PMID: 21441909

A cryptic sensor for HIV-1 activates antiviral innate immunity in dendritic cells. Manel N, Hogstad B, Wang Y, Levy DE, Unutmaz D, Littman DR. Nature. 2010 Sep 9;467(7312):214-7. PMID: 20829794

Click here to see all publications in PubMed