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 β(2) family of integrins as regulators of γδ T cells. β(2)-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 β(2)-integrin–deficient IL-17(+) cells compared to their wild-type counterparts. Indeed, β(2)-integrin–deficient Vγ6(+) cells from the lungs showed reduced apoptosis ex vivo, suggesting that increased survival contributes to the accumulation of these cells in β(2)-integrin–deficient tissues. Furthermore, our data revealed an unexpected role for β(2) integrins in promoting the thymic development of the IFNγ-producing CD27(+) Vγ4(+) γδ T cell subset. Together, our data reveal that β(2) 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.