MR1 uses an endocytic pathway to activate mucosal-associated invariant T cells.
Like CD1d-restricted iNKT cells, mucosal-associated invariant T cells (MAITs) are "innate" T cells that express a canonical TCRalpha chain, have a memory phenotype, and rapidly secrete cytokines upon TCR ligation. Unlike iNKT cells, MAIT cells require the class Ib molecule MHC-related protein I (MR1), B cells, and gut flora for development and/or expansion, and they preferentially reside in the gut lamina propria. Evidence strongly suggests that MAIT cell activation is ligand-dependent, but the nature of MR1 ligand is unknown. In this study, we define a mechanism of endogenous antigen presentation by MR1 to MAIT cells. MAIT cell activation was dependent neither on a proteasome-processed ligand nor on the chaperoning by the MHC class I peptide loading complex. However, MAIT cell activation was enhanced by overexpression of MHC class II chaperones Ii and DM and was strikingly diminished by silencing endogenous Ii. Furthermore, inhibiting the acidification of the endocytic compartments reduced MR1 surface expression and ablated MAIT cell activation. The importance of the late endosome for MR1 antigen presentation was further corroborated by the localization of MR1 molecules in the multivesicular endosomes. These findings demonstrate that MR1 traffics through endocytic compartments, thereby allowing MAIT cells to sample both endocytosed and endogenous antigens.
Huang
Shouxiong
S
Department of Pathology and Immunology, Washington University, St. Louis, MO 63110, USA.
Gilfillan
Susan
S
Kim
Sojung
S
Thompson
Bruce
B
Wang
Xiaoli
X
Sant
Andrea J
AJ
Fremont
Daved H
DH
Lantz
Olivier
O
Hansen
Ted H
TH
D000071181:ATP Binding Cassette Transporter, Subfamily B, Member 2; D018528:ATP-Binding Cassette Transporters / Q000235:genetics; D000818:Animals; D003001:Cloning, Molecular; D004705:Endocytosis; D015395:Histocompatibility Antigens Class I / Q000235:genetics / Q000502:physiology*; D018928:Immunity, Mucosal; D008213:Lymphocyte Activation; D051379:Mice; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D015778:Minor Histocompatibility Antigens; D034622:RNA Interference; D013601:T-Lymphocytes / Q000276:immunology* / Q000648:ultrastructure
D000071181:ATP Binding Cassette Transporter, Subfamily B, Member 2; D018528:ATP-Binding Cassette Transporters; D015395:Histocompatibility Antigens Class I; D015778:Minor Histocompatibility Antigens; C490628:Mr1 protein, mouse; C486171:Tap1 protein, mouse