Dan R. Littman, MD, PhD

Dan R LittmanHelen 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
E-mail: Dan.Littman@med.nyu.edu
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

Research Summary:

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.

Selected Publications: