Journal
BLOOD
Volume 121, Issue 4, Pages 614-623Publisher
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2012-09-456095
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Funding
- Inserm
- ANR (France) [ANR-08-MIEN-012-01]
- XLP Research Trust (United Kingdom)
- European Research Council [ERC-2009-AdG_20090506, FP7-249816]
- Ministere de la Recherche et de l'Ecole Polytechnique (France)
- Fondation ARC pour la Recherche sur le Cancer (ARC
- France)
- ARC
- ANR (France)
- Ligue Contre le Cancer (France)
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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 conditions including the XIAP immunodeficiency. (Blood. 2013; 121(4): 614-623)
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