β2 Integrins differentially regulate γδ T cell subset thymic development and peripheral maintenance.

The γδ T cells reside predominantly at barrier sites and play essential roles in immune protection against infection and cancer. Despite recent advances in the development of γδ T cell immunotherapy, our understanding of the basic biology of these cells, including how their numbers are regulated in vivo, remains poor. This is particularly true for tissue-resident γδ T cells. We have identified the β2 family of integrins as regulators of γδ T cells. β2-integrin-deficient mice displayed a striking increase in numbers of IL-17-producing Vγ6Vδ1+ γδ T cells in the lungs, uterus, and circulation. Thymic development of this population was normal. However, single-cell RNA sequencing revealed the enrichment of genes associated with T cell survival and proliferation specifically in β2-integrin-deficient IL-17+ cells compared to their wild-type counterparts. Indeed, β2-integrin-deficient Vγ6+ cells from the lungs showed reduced apoptosis ex vivo, suggesting that increased survival contributes to the accumulation of these cells in β2-integrin-deficient tissues. Furthermore, our data revealed an unexpected role for β2 integrins in promoting the thymic development of the IFNγ-producing CD27+ Vγ4+ γδ T cell subset. Together, our data reveal that β2 integrins are important regulators of γδ T cell homeostasis, inhibiting the survival of IL-17-producing Vγ6Vδ1+ cells and promoting the thymic development of the IFNγ-producing Vγ4+ subset. Our study introduces unprecedented mechanisms of control for γδ T cell subsets.

Citation

Claire L McIntyre, Leticia Monin, Jesse C Rop, Thomas D Otto, Carl S Goodyear, Adrian C Hayday, Vicky L Morrison. β2 Integrins differentially regulate γδ T cell subset thymic development and peripheral maintenance. Proceedings of the National Academy of Sciences of the United States of America. 2020 Sep 08;117(36):22367-22377

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PMID: 32848068

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