Human iNKT and MAIT cells exhibit a PLZF-dependent proapoptotic propensity that is counterbalanced by XIAP

• Published in: Blood Vol. 121; no. 4; pp. 614 - 623
• Main Authors: Gérart, Stéphane, Sibéril, Sophie, Martin, Emmanuel, Lenoir, Christelle, Aguilar, Claire, Picard, Capucine, Lantz, Olivier, Fischer, Alain, Latour, Sylvain
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 24.01.2013
• Subjects: Apoptosis - genetics; Apoptosis - immunology; Apoptosis Regulatory Proteins - genetics; Apoptosis Regulatory Proteins - immunology; Gene Expression Regulation; Humans; Kruppel-Like Transcription Factors - genetics; Kruppel-Like Transcription Factors - immunology; Lymphocyte Count; Natural Killer T-Cells - immunology; Natural Killer T-Cells - metabolism; Phenotype; Promyelocytic Leukemia Zinc Finger Protein; Receptors, Antigen, T-Cell, alpha-beta - genetics; Receptors, Antigen, T-Cell, alpha-beta - metabolism; T-Lymphocyte Subsets - immunology; T-Lymphocyte Subsets - metabolism; X-Linked Inhibitor of Apoptosis Protein - genetics; X-Linked Inhibitor of Apoptosis Protein - immunology
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2012-09-456095

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. •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.