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.