title: Stepwise development of MAIT cells in mouse and human.
abstract: Mucosal-associated invariant T (MAIT) cells display two evolutionarily conserved features: an invariant T cell receptor (TCR)alpha (iTCRalpha) chain and restriction by the nonpolymorphic class Ib major histocompatibility complex (MHC) molecule, MHC-related molecule 1 (MR1). MR1 expression on thymus epithelial cells is not necessary for MAIT cell development but their accumulation in the gut requires MR1 expressing B cells and commensal flora. MAIT cell development is poorly known, as these cells have not been found in the thymus so far. Herein, complementary human and mouse experiments using an anti-humanValpha7.2 antibody and MAIT cell-specific iTCRalpha and TCRbeta transgenic mice in different genetic backgrounds show that MAIT cell development is a stepwise process, with an intra-thymic selection followed by peripheral expansion. Mouse MAIT cells are selected in an MR1-dependent manner both in fetal thymic organ culture and in double iTCRalpha and TCRbeta transgenic RAG knockout mice. In the latter mice, MAIT cells do not expand in the periphery unless B cells are added back by adoptive transfer, showing that B cells are not required for the initial thymic selection step but for the peripheral accumulation. In humans, contrary to natural killer T (NKT) cells, MAIT cells display a naïve phenotype in the thymus as well as in cord blood where they are in low numbers. After birth, MAIT cells acquire a memory phenotype and expand dramatically, up to 1%-4% of blood T cells. Finally, in contrast with NKT cells, human MAIT cell development is independent of the molecular adaptor SAP. Interestingly, mouse MAIT cells display a naïve phenotype and do not express the ZBTB16 transcription factor, which, in contrast, is expressed by NKT cells and the memory human MAIT cells found in the periphery after birth. In conclusion, MAIT cells are selected by MR1 in the thymus on a non-B non-T hematopoietic cell, and acquire a memory phenotype and expand in the periphery in a process dependent both upon B cells and the bacterial flora. Thus, their development follows a unique pattern at the crossroad of NKT and gammadelta T cells.
authors.affiliation: Laboratoire d'Immunologie, Institut Curie, Paris, France.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Martin
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Treiner
authors.forename: Livine
authors.initials: L
authors.lastname: Duban
authors.forename: Lucia
authors.initials: L
authors.lastname: Guerri
authors.forename: Hélène
authors.initials: H
authors.lastname: Laude
authors.forename: Cécile
authors.initials: C
authors.lastname: Toly
authors.forename: Virginie
authors.initials: V
authors.lastname: Premel
authors.forename: Anne
authors.initials: A
authors.lastname: Devys
authors.forename: Ivan C
authors.initials: IC
authors.lastname: Moura
authors.forename: Florence
authors.initials: F
authors.lastname: Tilloy
authors.forename: Stéphane
authors.initials: S
authors.lastname: Cherif
authors.forename: Gabriella
authors.initials: G
authors.lastname: Vera
authors.forename: Sylvain
authors.initials: S
authors.lastname: Latour
authors.forename: Claire
authors.initials: C
authors.lastname: Soudais
authors.forename: Olivier
authors.initials: O
authors.lastname: Lantz
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000502:physiology; D002648:Child; D005312:Fetal Blood / Q000276:immunology; D041981:Gastrointestinal Tract / Q000166:cytology / Q000276:immunology / Q000382:microbiology; D015395:Histocompatibility Antigens Class I / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D018928:Immunity, Mucosal / Q000276:immunology*; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D015778:Minor Histocompatibility Antigens; D055611:Natural Killer T-Cells / Q000502:physiology*; D000075722:Promyelocytic Leukemia Zinc Finger Protein; D016693:Receptors, Antigen, T-Cell, alpha-beta; D016176:T-Lymphocyte Subsets / Q000502:physiology*; D013601:T-Lymphocytes; D013950:Thymus Gland / Q000166:cytology / Q000276:immunology*
chemical_list: D015395:Histocompatibility Antigens Class I; D051741:Kruppel-Like Transcription Factors; C094840:MR1 protein, human; D015778:Minor Histocompatibility Antigens; D000075722:Promyelocytic Leukemia Zinc Finger Protein; D016693:Receptors, Antigen, T-Cell, alpha-beta; C513267:Zbtb16 protein, mouse