Remy Bosselut, M.D., Ph.D.
Laboratory of Immune Cell Biology
Building 37, Room 3032A
Bethesda, MD 20892-4259
We study the differentiation and function of T lymphocytes (T cells), and specifically of CD4+ helper T cells, which are essential for immune responses. CD4+ lymphopenia underlies infectious complications and death in HIV-induced immunodeficiency, and is a chief cause of morbidity and mortality after myeloablative cancer chemotherapy. CD4+ T cells typically recognize peptide antigens bound to class II Major Histocompatibility Complex molecules (MHC-II). Together with CD8+ T cells, which recognize MHC-I bound antigens and differentiate into cytotoxic effectors, they form the bulk of T cell populations in lymphoid organs and tissues. Most of our recent research has focused on the transcriptional control of CD4+ T cell development in the thymus and of their functions during immune responses. We have found that the zinc finger transcription factor Thpok promotes CD4+ T cell differentiation in the thymus and inhibits expression of CD8+-lineage genes, including of the canonical CD8+-lineage transcription factor Runx3 (reviewed in Carpenter and Bosselut, 2010, Nat Immunol, 11:666).
Our current research builds on these earlier findings and focuses on three key areas.
1-Transcriptional mechanisms underlying helper vs. cytotoxic effector programs in mature T cells. We have found that Thpok, together with the related transcription factor LRF, is needed to pre-program thymocytes for helper functions and to maintain many critical aspects of helper differentiation in vivo, including the differentiation of Th1 and Th2 effector T cells, which are required for defenses against intra-cellular pathogens and helminths, respectively (Carpenter et al., 2012; Vacchio et al., 2014). Current research investigates how these factors regulate T cell functions in vivo, with specific interest in their potential role in responses against tumors.
2- The transcriptional circuitry that promotes CD4+ T cell differentiation in the thymus. One critical characteristic of T cells is the strict correspondence between MHC specificity and CD4 or CD8 expression, so that MHC II-restricted thymocytes become CD4+ T cells, whereas MHC I-restricted thymocytes become CD8+ T cells. While this correspondence is necessary for the proper function of the immune system, it remains unclear how it is established during T cell development in the thymus (discussed in Xiong and Bosselut, 2012, Curr Opin Immunol, 24:139). Using a variety of genetic approaches, we are working to identify transcription factors involved in this process, their target genes and their connections within the thymocyte transcriptional network.
3-Chromatin control of gene expression in developing T cells. In addition to transcription factors, histones, proteins that ‘package’ DNA into chromatin, are essential for proper transcription control. Much attention has focused on a specific histone post-translational modification, the methylation of histone H3 lysine 27 (H3K27), which marks silent genes. To get insight into the contribution of H3K27 methylation-demethylation to gene expression, we have inactivated the two known H3K27 demethylases, Jmjd3 and Utx, in developing T cells. We have found that these enzymes are essential for gene expression during CD4+ T cell differentiation, notably for that of S1pr1, encoding a sphingosine phosphate receptor needed for thymic egress (Manna et al., 2015). Current research is directed at understanding the mechanistic underpinnings of the functions of these enzymes.
Manna S, Kim JK, Baugé C, Cam M, Zhao Y, Shetty J, Vacchio MS, Castro E, Tran B, Tessarollo L, Bosselut R. Histone H3 Lysine 27 demethylases Jmjd3 and Utx are required for T-cell differentiation. Nat Commun. 2015;6:8152.
Vacchio MS, Wang L, Bouladoux N, Carpenter AC, Xiong Y, Williams LC, Wohlfert E, Song KD, Belkaid Y, Love PE, Bosselut R. A ThPOK-LRF transcriptional node maintains the integrity and effector potential of post-thymic CD4+ T cells. Nat Immunol. 2014;15(10):947-56.
Carpenter AC, Grainger JR, Xiong Y, Kanno Y, Chu HH, Wang L, Naik S, dos Santos L, Wei L, Jenkins MK, O'Shea JJ, Belkaid Y, Bosselut R. The transcription factors Thpok and LRF are necessary and partly redundant for T helper cell differentiation. Immunity. 2012;37(4):622-33.
Wang L, Wildt KF, Zhu J, Zhang X, Feigenbaum L, Tessarollo L, Paul WE, Fowlkes BJ, Bosselut R. Distinct functions for the transcription factors GATA-3 and ThPOK during intrathymic differentiation of CD4(+) T cells. Nat Immunol. 2008;9(10):1122-30.
Sun G, Liu X, Mercado P, Jenkinson SR, Kypriotou M, Feigenbaum L, Galéra P, Bosselut R. The zinc finger protein cKrox directs CD4 lineage differentiation during intrathymic T cell positive selection. Nat Immunol. 2005;6(4):373-81.
Related Scientific Focus Areas
Molecular Biology and Biochemistry
This page was last updated on June 15th, 2017