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.
M.D., Ph.D., 1980 Washington University, St. Louis
Inflammation, HIV, T cells, microbiota, Th17, epigenetic regulation, lncRNAs
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
Tel: (212) 263-7520
Microbiota-regulated immunity, epigenetic regulation of T cell differentiation, and mechanisms of 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 mechanisms for establishing epigenetic programs in maturing T cells.
Our studies on peripheral T cells have led to the identification of the nuclear receptor RORgt, that is required for the differentiation of Th17 cells, critical cells in mucosal defense and in inflammatory diseases. We are investigating how distinct commensal microbes influence the differentiation of Th17 cells and other types of T cells, including regulatory T cells (Treg), in different regions of the intestine. A major goal is to determine how intestinal commensal bacteria can trigger systemic T cell-mediated autoimmune diseases, and we are investigating the roles of diverse myeloid cell types, innate lymphoid cells (e.g. ILC3 that are also dependent on RORgt), and cytokines in the polarization of the multiple types of T cells. We are characterizing functions of RORgt in multiple cell types, including ILC3 and mucosal regulatory T cells, and focusing on the role of a RORgt-associated RNA helicase and a long non-coding RNA in the differentiation of Th17 cells.
A distinct area of interest of the laboratory is the elucidation of mechanisms by which the Human Immunodeficiency Virus is transmitted and damages the immune system. HIV fuses to target cells after binding to CD4 and CCR5. Infection of T cells is enhanced if HIV is first bound to dendritic cells and then presented to the target cells. 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 and innate immune system activation in vivo in HIV infection and pathogenesis. Such models may provide important insight into mechanisms of pathogenesis and development of new therapies and vaccines.
- 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
- Yang, Y., Torchinsky, M.B., Gobert, M., Xiong, H., Xu, M., Linehan, J.L., Alonzo, F., Ng, C., Chen, A., Lin, X., Sczesnak, A., Liao, J.J., Torres, V.J., Jenkins, M.K., Lafaille, J.J., Littman, D.R. (2014) Focused specificity of intestinal TH17 cells towards commensal bacterial antigens. Nature 510, 152-6. PMID: 24739972
- Sellars, M., Huh, J.R., Day, K., Galan, C., Gobeil, S., Absher, D., Green, M.R. & Littman, D.R. (2015) Regulation of DNA methylation dictates Cd4 gene expression during development of helper and cytotoxic T cell lineages. Nature Immunology, 16, 746-54. PMID: 26030024
- Sano, T., Huang, W., Hall, J.A., Yang, Y., Chen, A., Gavzy, S.J., Lee, J.Y., Ziel, J., Miraldi, E., Bonneau, R. & Littman, D.R. (2015) An IL-23R/IL-22 circuit regulates epithelial serum amyloid A to promote local effector Th17 responses. Cell, 163, 381-93. PMID: 26411290
- Huang, W., Thomas, B., Gavzy, S.J., Wu, L., Kim, S.V., Rigo, F., Meadows, S., Montoya, N.R., Herrera, N., Domingos, A.I., Rastinejad, F., Myers, R.M., Fuller-Pace, F.V., Acuto, O. & Littman, D.R. (2015) DDX5 and its associated lncRNA Rmrp modulate Th17 cell effector functions. Nature, 528, 517-522. PMID: 26675721