Inhibitor of apoptosis proteins 1 and 2 are required for the homeostasis of murine RORγt⁺ γδ T cells

Abstract

RORγt⁺ γδ T cells, known as γδT17, are an innate-like subset of T cells that produce interleukin (IL)-17A and initiate type 3 immune responses during infections or autoimmune pathologies. Herein we show that the cellular inhibitor of apoptosis proteins cIAP1 and 2 are required for the peripheral homeostasis of γδT17 but not for their thymic development. γδT17 cells that were deficient in both cIAP1 and 2 were profoundly reduced in the peripheral lymph nodes and skin. Likewise, both RORγt⁺ innate lymphoid (ILC3) cells and RORγt⁺ Tbet⁺ γδ T cells were reduced in the lamina propria of adult mice. Further, cIAP1 and 2 were required for the expression of the transcription factors RORγt and cMAF in γδT17 during neonatal and adult life. Single deficiency of either cIAP1 or 2 did not affect the homeostasis or transcription factor profile of γδT17. Inhibition of the kinase RIPK1 partially reversed the deficiency of γδT17 cells but not the downregulation of RORγt in cIAP1 and cIAP2 double deficient animals. Further, bone marrow reconstitutions and transfer of neonatal γδ T cells to RAG1^-/- hosts showed that both intrinsic and extrinsic factors contribute to the loss in γδT17 cells lacking cIAP1 and cIAP2. Deficiency of γδT17 cells in cIAP1 and cIAP2 double deficient animals, or the presence of functionally defective γδT17 cells did not confer protection against IMQ-induced psoriasis. Collectively, our data reveal a previously undescribed role for cIAP1 and cIAP2 in the homeostasis of γδT17 and ILC3 cells.