title: Human iNKT and MAIT cells exhibit a PLZF-dependent proapoptotic propensity that is counterbalanced by XIAP.
abstract: 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.
authors.affiliation: Unité Inserm 768, Laboratoire du Développement Normal et Pathologique du Système Immunitaire, Hôpital Necker Enfants-Malades, Paris, France.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Gérart
authors.forename: Sophie
authors.initials: S
authors.lastname: Sibéril
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Martin
authors.forename: Christelle
authors.initials: C
authors.lastname: Lenoir
authors.forename: Claire
authors.initials: C
authors.lastname: Aguilar
authors.forename: Capucine
authors.initials: C
authors.lastname: Picard
authors.forename: Olivier
authors.initials: O
authors.lastname: Lantz
authors.forename: Alain
authors.initials: A
authors.lastname: Fischer
authors.forename: Sylvain
authors.initials: S
authors.lastname: Latour
mesh_terms: D017209:Apoptosis / Q000235:genetics / Q000276:immunology; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000276:immunology; D005786:Gene Expression Regulation; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000235:genetics* / Q000276:immunology; D018655:Lymphocyte Count; D055611:Natural Killer T-Cells / Q000276:immunology / Q000378:metabolism*; D010641:Phenotype; D000075722:Promyelocytic Leukemia Zinc Finger Protein; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics / Q000378:metabolism; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism*; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000235:genetics* / Q000276:immunology
chemical_list: D051017:Apoptosis Regulatory Proteins; D051741:Kruppel-Like Transcription Factors; D000075722:Promyelocytic Leukemia Zinc Finger Protein; D016693:Receptors, Antigen, T-Cell, alpha-beta; D051636:X-Linked Inhibitor of Apoptosis Protein; C092037:ZBTB16 protein, human