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J Exp Med. 2019 Aug 21. pii: jem.20190993. doi: 10.1084/jem.20190993. [Epub ahead of print]

IL-2 production by self-reactive CD4 thymocytes scales regulatory T cell generation in the thymus.

Author information

1
Howard Hughes Medical Institute and Immunology Program at Sloan Kettering Institute, and Ludwig Center for Cancer Immunotherapy, Memorial Sloan Kettering Cancer Center, New York, NY.
2
Program for Computational and Systems Biology, Memorial Sloan Kettering Cancer Center, New York, NY.
3
Immunology and Microbial Pathogenesis Program, Weill Cornell Graduate School of Medical Sciences, New York, NY.
4
Immunodynamics Group, Cancer and Inflammation Program, National Cancer Institute, National Institutes of Health, Bethesda, MD.
5
Howard Hughes Medical Institute and Immunology Program at Sloan Kettering Institute, and Ludwig Center for Cancer Immunotherapy, Memorial Sloan Kettering Cancer Center, New York, NY rudenska@mskcc.org.

Abstract

Regulatory T (T reg) cells, a specialized subset of CD4+ T cells, are essential to prevent fatal autoimmunity. Expression of the T reg lineage-defining transcription factor Foxp3, and therefore their differentiation in the thymus, is dependent upon T cell receptor (TCR) and interleukin-2 (IL-2) signaling. Here, we report that the majority of IL-2-producing cells in the thymus are mature CD4 single-positive (CD4SP) thymocytes and that continuous IL-2 production sustained thymic T reg cell generation and control of systemic immune activation. Furthermore, single-cell RNA sequencing analysis of CD4 thymocyte subsets revealed that IL-2 was expressed in self-reactive CD4SP thymocytes, which also contain T reg precursor cells. Thus, our results suggest that the thymic T reg cell pool size is scaled by a key niche factor, IL-2, produced by self-reactive CD4SP thymocytes. This IL-2-dependent scaling of thymic T reg cell generation by overall self-reactivity of a mature post-selection thymic precursor pool may likely ensure adequate control of autoimmunity.

PMID:
31434685
DOI:
10.1084/jem.20190993

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