The Inhibitory Receptor BTLA Controls γδ T Cell Homeostasis and Inflammatory Responses

gamma delta T cells rapidly secrete inflammatory cytokines at barrier sites that aid in protection from pathogens, but mechanisms limiting inflammatory damage remain unclear. We found that retinoid-related orphan receptor gamma-t (ROR gamma t) and interleukin-7 (IL-7) influence gamma delta T cell homeostasis and function by regulating expression of the inhibitory receptor, B and T lymphocyte attenuator (BTLA). The transcription factor ROR gamma t, via its activating function-2 domain, repressed Btla transcription, whereas IL-7 increased BTLA levels on the cell surface. BTLA expression limited gamma delta T cell numbers and sustained normal gamma delta T cell subset frequencies by restricting IL-7 responsiveness and expansion of the CD27(-)ROR gamma t(+) population. BTLA also negatively regulated IL-17 and TNF production in CD27(-) gamma delta T cells. Consequently, BTLA-deficient mice exhibit enhanced disease in a gamma delta T cell-dependent model of dermatitis, whereas BTLA agonism reduced inflammation. Therefore, by coordinating expression of BTLA, ROR gamma t and IL-7 balance suppressive and activation stimuli to regulate gamma delta T cell homeostasis and inflammatory responses.