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. In addition, CD4+ T cells are involved in tumor control and clinical studies have established their potential as anti-tumor agents. 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.
Current research focuses on three key areas.
1) CD4+ helper T cell development in the thymus. CD4+ T cells differentiate in the thymus from CD4+CD8+ “double-positive” thymocytes that have received positive selection signals from MHC-II-peptide antigens. We are investigating how the transcriptomic and epigenomic program characteristic of CD4+ T cells is established in these precursors. This includes studying the mechanisms of action of the zinc finger transcription factor Thpok, which is necessary for intrathymic CD4+ T cell development and for the continued integrity of mature CD4+ T cells. Additionally, we are using a combination of high-throughput gene expression analyses (including single-cell RNA sequencing) and genetic approaches to identify new transcription factors and signaling pathways involved in the emergence of the CD4+-specific transcriptome.
2) Transcriptional control of the “fitness” of CD4+ T cell responses. We recently found that the transcription factor Thpok is necessary for the emergence of memory CD4+ T cells during infection, and for their function during recall responses (Ciucci et al, Immunity, 2019). Our studies in this field integrate gene expression analyses and genetics (including Crispr-Cas9 genome editing) to decipher the transcriptional network that controls the functionality of CD4+ T cell responses in acute and chronic infection models.
3) CD4+ T cell responses to cancer. Even though most current tumor immunotherapy strategies rely on cytolytic CD8+ T cells, CD4+ T cells are attractive tools to treat cancer because of their diverse functions, including cytokine production (e.g., IFN-gamma), help to CD8+ T cells, or impact on blood vessel permeability and angiogenesis. However, subsets of CD4+ T cells, including regulatory T cells, can restrain anti-tumor immunity and promote tumor growth. We are developing experimental models to understand the function of CD4+ T cells in the tumor micro-environment and to design strategies to harness their anti-tumor potential.
- 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 Tuesday, April 5, 2022