XIAP promotes the expansion and limits the contraction of CD8 T cell response through cell extrinsic and intrinsic mechanisms respectively

XIAP is an endogenous inhibitor of cell death and inactivating mutations of XIAP are responsible for X-linked lymphoproliferative disease (XLP-2) and primary immunodeficiency, but the mechanism(s) behind these contradictory outcomes have been unclear. We report that during infection of macrophages and dendritic cells with various intracellular bacteria, XIAP restricts cell death and secretion of IL-1 & beta; but promotes increased activation of NF & kappa;B and JNK which results in elevated secretion of IL-6 and IL-10. Poor secretion of IL-6 by Xiap-deficient antigen presenting cells leads to poor expansion of recently activated CD8 T cells during the priming phase of the response. On the other hand, Xiap-deficient CD8 T cells displayed increased proliferation and effector function during the priming phase but underwent enhanced contraction subsequently. Xiap-deficient CD8 T cells underwent skewed differentiation towards short lived effectors which resulted in poor generation of memory. Consequently Xiap-deficient CD8 T cells failed to provide effective control of bacterial infection during re-challenge. These results reveal the temporal impact of XIAP in promoting the fitness of activated CD8 T cells through cell extrinsic and intrinsic mechanisms and provide a mechanistic explanation of the phenotype observed in XLP-2 patients. Author summaryDeath of host cells is an important physiological mechanism to promote health of an organism, however overt death of host cells can lead to tissue toxicity. X-linked inhibitor of apoptosis (XIAP) is an endogenous inhibitor of cell death that inhibits various enzymes (caspases) that are involved in cell death. In humans, inactivating mutations of XIAP result in X-linked lymphoproliferative disease-2 (XLP-2) which is characterized by a state of lymphoproliferation and immunodeficiency, but the mechanisms are not fully understood. In this report we have tested the role of XIAP in innate and acquired immune response against two intracellular bacteria and show that XIAP promotes the development of acquired immune response through separate effects on the innate and acquired immune system. While XIAP promotes the expression of IL-6 by cells of the innate immune system which promotes the survival of activated T cells, XIAP also inhibits the culling of activated T cells through a cell intrinsic mechanism. These results provide a new insight into the mechanisms that lead to the development of XLP-2.