No abstract

Key Points• Human innate-like lymphocytes, iNKT and MAIT cells exhibit a proapoptotic phenotype associated with increased levels of caspases.• The proapoptotic feature of iNKT and MAIT cells depends on the transcription factor PLZF and is regulated by the anti-apoptotic factor XIAP. Invariant natural killer (iNKT) T cells and mucosal-associated invariant T (MAIT) cells represent peculiar T-lymphocyte subpopulations with innate-like properties that differ from conventional T cells. iNKT are reduced in the primary immunodeficiency caused by mutations in the X-linked inhibitor of apoptosis (XIAP). By studying the mechanism of this depletion, we herein report that iNKT cells exhibit a high susceptibility to apoptosis that is not observed with conventional T cells. Elevated expression of caspases 3 and 7 accounts for the proapoptotic phenotype of iNKT cells, which is inhibited by XIAP although it exerts a moderate effect in conventional T cells. Similarly, MAIT cells exhibit a proapoptotic propensity with elevated expression of activated caspases and are decreased in XIAP-deficient individuals. Knockdown of the transcription factor PLZF/ ZBTB-16, which is involved in the effector program of iNKT cells, diminishes their proapoptotic phenotype. Conversely, overexpression of PLZF/ZBTB-16 in conventional T cells leads to a proapoptotic phenotype. Our findings identify a previously unknown pathway of regulation of innate-like T-cell homeostasis depending on XIAP and PLZF. The proapoptotic feature of iNKT cells also gives a reliable explanation of their exhaustion observed in different human IntroductionInvariant natural killer T (iNKT) lymphocytes represent a distinct T-cell lineage with innate-like traits differing from conventional T cells. 1 In humans, iNKT cells express an invariant (or semiinvariant in mice) TCR made of the V␣24/J␣18/V␤11 rearrangements, which recognize glycosphingolipids from foreign and self origin presented by the MHC class I-like monomorphic molecule CD1d. 2 Several factors required for the development of iNKT cells but not of conventional T cells have been identified including the SLAM family receptors, the SLAM-associated protein (SAP) and transcription factors, such as NF-B, Egr2, HEB, and PLZF. 3 Functionally, iNKT cells are characterized by their ability to rapidly release large amounts of T helper (Th) type 1 (Th1), Th2, and Th17 cytokines and chemokines when activated. In accordance with these unique features, many studies in mice have demonstrated their involvement in a variety of immune responses and immunopathologic conditions. 1 Recently, a second invariant T-cell subpopulation, the mucosal associated invariant T (MAIT) cells was identified both in humans and mice. [4][5][6] These cells express a semi-invariant TCR made of V␣7.2/J␣33 rearrangements and share with iNKT cells several developmental, functional, and phenotypical features. 7,8 In humans, our knowledge of the biology of iNKT cells is more limited. Indeed, iNKT cells are present in very variable albeit low proportions in con...