We investigate the transcriptional control of T cell development and function. We are specifically interested in the gene expression programs that (i) control the choice by T cell precursors of the CD4 or CD8 lineage, and (ii) perpetuate lineage differentiation in mature cells. <p>Most T cells recognize peptide antigens presented by class I (MHC-I) or class II (MHC-II) classical Major Histocompatibility Complex molecules. T cell recognition of MHC-peptide complexes is aided by two surface glycoproteins called coreceptors: 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 and functional differentiation. That is, the general rule is that MHC I-specific T cells are CD4-CD8+ and cytotoxic (CD8 cells), whereas MHC II-specific T cells are CD4+CD8- and helper or regulatory (CD4 cells). This double correspondence is essential to the proper function of the immune system and is established in the thymus, where CD4 and CD8 T cells emerge as separate lineages from precursors expressing both CD4 and CD8 (double positive, DP). Deciphering the transcriptional regulatory networks that decide and maintain CD4-CD8 lineage differentiation is the target of our current research. <p>Our efforts during the last three years have focused on the function of two zinc finger transcription factors, Gata3 and Thpok (also known as Zbtb7b or cKrox) in CD4 cell differentiation, and on how they act in concert with transcriptional regulators of the Runx family to decide CD4-CD8 choice in the thymus. Notably, we found that while both Gata3 and Thpok are necessary for the development of CD4 T cells, they have distinct functions in this process (Wang et al, 2008, Nat. Immunol.). That is, Gata3 is required earlier than Thpok, and is notably needed for Thpok expression (a finding that we have recently extended to a special subset of T cells knows as NK T cells, that act at the cross-roads between innate and adaptive immune responses). Thpok, in contrast, is not needed to promote Gata3 expression and principally serves to inhibit CD8-lineage differentiation. Based on these findings, we proposed that Gata3 and Thpok act as specification and commitment factors, respectively, during CD4-lineage differentiation in the thymus, in agreement with other reports published simultaneously. We are currently evaluating how these factors promote the expression of other genes characteristic of the CD4 lineage. <p>The hypothesis that Thpok serves primarily to repress the expression of CD8-lineage genes fits with results from our earlier experiments assessing the function of Thpok in mature T cells (Jenkinson et al., 2007). Using Thpok retroviral transduction into CD8 T cells (in which this factor is normally not expressed) we had found that Thpok represses the expression of CD8 and of characteristic cytotoxic genes, including those encoding perforin and granzyme B. Reciprocally, we have recently investigated the function of Thpok in mature CD4 T cells (in which it is normally expressed) using loss-of-function approaches, by generating hypomorphic and conditional ('floxed') Thpok alleles (Wang et al., 2008, Immunity). We found that Thpok maintains the CD4 'identity', and notably that its deletion in mature (post-thymic) CD4 T cells that had developed as Thpok-sufficient results in the re-expression of CD8 and of cytotoxic genes. We further showed that such aberrant expression depends on the activity of Runx transcriptional regulators. Indeed, Thpok-deficient CD4 cells abnormally express Runx3, a member of this family normally present in CD8 but not CD4 cells and essential to the proper differentiation of CD8-lineage cells in the thymus. Thus, Thpok functions in CD4 T cells to permanently repress expression of CD8 lineage genes. <p>Altogether, these findings define Thpok as a major commitment factor for the CD4 lineage, and demonstrate that similar gene networks control the emergence of CD4 and CD8 lineages in the thymus, and their persistence in mature post-thymic T cells. We are currently examining whether and how Thpok contributes to expression of CD4-lineage genes in peripheral T cells. We are also expanding these studies to identify factors that control the expression of Thpok and Runx3.
| Ciucci, Thomas; Vacchio, Melanie S; Bosselut, Rémy (2017) A STAT3-dependent transcriptional circuitry inhibits cytotoxic gene expression in T cells. Proc Natl Acad Sci U S A 114:13236-13241 |
| Bosselut, Rémy; Vacchio, Melanie S (2016) Preface. T-Cell Development. Methods Mol Biol 1323:v-vi |
| Vacchio, Melanie S; Ciucci, Thomas; Bosselut, Rémy (2016) 200 Million Thymocytes and I: A Beginner's Survival Guide to T Cell Development. Methods Mol Biol 1323:3-21 |
| Carpenter, Andrea C; Kim, Jong Kyong; Bosselut, Rémy (2016) Purification of Thymocyte and T Cell Subsets. Methods Mol Biol 1323:87-97 |
| Zhang, Shaofei; Zhu, Iris; Deng, Tao et al. (2016) HMGN proteins modulate chromatin regulatory sites and gene expression during activation of naïve B cells. Nucleic Acids Res : |
| Wohlfert, Elizabeth A; Carpenter, Andrea C; Belkaid, Yasmine et al. (2016) In Vitro Analyses of T Cell Effector Differentiation. Methods Mol Biol 1323:117-28 |
| Ciucci, Thomas; Vacchio, Melanie S; Bosselut, Rémy (2016) Genetic Tools to Study T Cell Development. Methods Mol Biol 1323:35-45 |
| Vacchio, Melanie S; Bosselut, Rémy (2016) What Happens in the Thymus Does Not Stay in the Thymus: How T Cells Recycle the CD4+-CD8+ Lineage Commitment Transcriptional Circuitry To Control Their Function. J Immunol 196:4848-56 |
| Bosselut, Rémy (2016) Pleiotropic Functions of H3K27Me3 Demethylases in Immune Cell Differentiation. Trends Immunol 37:102-113 |
| Ciucci, Thomas; Bosselut, Rémy (2016) A long journey coming to fruition: In sight of the preselection T-cell repertoire. Eur J Immunol 46:539-42 |
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