We are interested in the transcriptional control of T cell development and function. Specifically, we study the gene expression programs that control the choice by intrathymic T cell precursors of the CD4 or CD8 lineage, and determine their distinctive functional responses. T cells are essential for immune responses. "Conventional" T cells recognize peptide antigens presented by class I (MHC-I) or class II (MHC-II) classical Major Histocompatibility Complex molecules, and express either of two surface glycoproteins (called coreceptors) that contribute to antigen recognition: CD4, which binds MHC-II, or CD8, which binds MHC-I. Coreceptor expression on mature T cells is mutually exclusive and strongly correlates with both MHC specificity. That is, the general rule is that MHC I-specific T cells are CD4-CD8+ (CD8 cells), whereas MHC II-specific T cells are CD4+CD8- (CD4 cells). We are interested in the development of CD4 T cells, which provide 'help'to other immune cells and are essential to control infections (they are the key target of the human immunodeficiency virus HIV). Work conducted in the laboratory over the past 18 months has addressed two key questions: how do CD4 cells develop in the thymus and why do they mount helper rather than cytotoxic responses. Our studies of CD4 T cell differentiation in the thymus have been focusing on three main issues. First, we previously identified the transcription factor Thpok, which is required for CD4 T cell differentiation and whose expression in T cells is specific of the CD4 lineage, as a major repressor of CD8-lineage gene expression and CD8 T cell differentiation. We are currently investigating the mechanistic bases of Thpok function in CD4-CD8 lineage differentiation using both biochemical and mouse genetics approaches. Second, previous studies, including from our laboratory, have shown that inducing the gene expression program characteristic of CD4-helper cell requires factors other than Thpok, including Gata3, Tox and E-box binding proteins E2A and HEB. Using mouse genetics and gene expression analyses, we are currently examining how these factors collaborate with Thpok during CD4 T cell differentiation. Third, we have found that Gata3 contributes to restrain CD8-lineage gene expression in developing CD4-lineage thymocytes, notably by repressing the gene encoding the transcription factor Runx3, a critical factor in CD8-lineage differentiation. We found that Gata3 binds the Runx3 gene, supporting the idea that its repressive effect on Runx3 is at least in part direct. In parallel with these studies, we have addressed the important question of whether (and how) the function of CD4 T cells was determined by the transcriptional network that directs their differentiation in the thymus. Indeed, CD4 and CD8 T cells typically perform distinct functions upon antigen encounter: whereas CD8 T cells differentiate into cytotoxic effectors, CD4 T cells provide help to other components on the immune system and have essential regulatory functions. We therefore asked the question of whether Thpok, which is required for the differentiation of MHC II-specific thymocytes into CD4 T cells, is also needed for their functional differentiation into helper cells. Unexpectedly, analyses in Thpok-deficient mice showed that this was not the case: even though Thpok-deficient cells exit the thymus as CD8 T cells and express cytotoxic genes, they retain most functions characteristic of helper T cells upon antigen activation. This includes the activation of genes characteristic of the CD4 lineage, including CD4 itself, Thpok and CD40L, a molecule essential to T cell interactions with B cells and dendritic cells. Using deep-sequencing analyses of chromatin modifications, we found that epigenetic reconfiguration at such loci during CD4-lineage differentiation in the thymus is largely independent from Thpok. Even more surprising was the observation that Thpok is not required for efficient helper effector responses against pathogens. These unexpected results led us to consider the possibility that factors related to Thpok might redundantly serve to promote helper effector differentiation. We found that this was indeed the case, as genetic disruption of genes encoding Thpok (Zbtb7b) and the related transcription factor LRF (Leukemia/Lymphoma Related Factor, encoded by Zbtb7a) resulted in a complete loss of helper T cell differentiation: that is, although Thpok and LRF-deficient MHC II-specific thymocytes still differentiated in the thymus into CD8 T cells, these cells were unable to express CD4-lineages genes and mount helper effector responses. These findings therefore demonstrate that the combined activity of Thpok and LRF is essential for the emergence of helper effector functions in T cells. We are currently investigating the mechanistic bases of this critical functions of Thpok and LRF.
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