We study immune responses, broadly speaking, but are most interested in the development and functions of T cells, a component of the immune system that is required for control of infections. We are specifically interested in CD4+ T cells, which in humans are the target of HIV, and are critical for most adaptive immune responses.
We have a comprehensive approach to research. Researchers in the lab integrate experimental approaches, including single cell and tissue “omics” analyses (which are a major focus of the lab), genetics, in vivo models of infection and tumor, and bioinformatics, e.g. modeling gene regulatory networks (1).
Current research is directed at three questions.
1-CD4+ T cell development in the thymus. Building on the laboratory’s long-standing interests (2), ongoing research investigates new signals or factors that direct CD4+ T cell development, and mechanisms that mediate the function of Thpok, a transcription factor required for the development of CD4+ T cells in the thymus and their post-thymic functions (3).
2-CD4+ T cell responses to infection and tumor. These studies have become a major area of focus in the laboratory. Using single-cell RNAseq and ATACseq, we recently characterized CD4+ T cell responses to infection (4-6) or tumors (7). Current research leverages newly developed experimental models to compare how CD4+ T cells control chronic infections and tumors, and to design strategies to harness their anti-tumor potential.
3-Role of the thymus in immune tolerance. Maintaining immune homeostasis, including tolerance to self-antigens and commensals at mucosal barriers, is a critical function of T cells. Recent (1 , 8) and ongoing studies investigate how the thymus contributes to tolerance through the deletion of self-reactive T cell precursors and generation of T cells with immunoregulatory functions.
1. L. B. Chopp et al., An Integrated Epigenomic and Transcriptomic Map of Mouse and Human αβ T Cell Development. Immunity 53, 1182-1201.e1188 (2020).
2. G. Sun et al., The zinc finger protein cKrox directs CD4 lineage differentiation during intrathymic T cell positive selection. Nat Immunol 6, 373-381 (2005).
3. Y. Gao et al., NuRD complex recruitment to Thpok mediates CD4(+) T cell lineage differentiation. Sci Immunol 7, eabn5917 (2022).
4. M. S. Vacchio et al., A Thpok-Directed Transcriptional Circuitry Promotes Bcl6 and Maf Expression to Orchestrate T Follicular Helper Differentiation. Immunity 51, 465-478.e466 (2019).
5. T. Ciucci et al., The Emergence and Functional Fitness of Memory CD4(+) T Cells Require the Transcription Factor Thpok. Immunity 50, 91-105.e104 (2019).
6. T. Ciucci et al., Dependence on Bcl6 and Blimp1 drive distinct differentiation of murine memory and follicular helper CD4+ T cells. J Exp Med 219, (2022).
7. A. Magen et al., Single-Cell Profiling Defines Transcriptomic Signatures Specific to Tumor-Reactive versus Virus-Responsive CD4(+) T Cells. Cell Rep 29, 3019-3032.e3016 (2019).
8. J. Nie et al., The transcription factor LRF promotes integrin β7 expression by and gut homing of CD8αα(+) intraepithelial lymphocyte precursors. Nat Immunol 23, 594-604 (2022).
- 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.
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Molecular Biology and Biochemistry
This page was last updated on Friday, April 21, 2023