Mouse endothelial cells cross-present lymphocyte-derived antigen on class I MHC via a TAP1- and proteasome-dependent pathway.
In vivo studies suggest that vascular endothelial cells (ECs) can acquire and cross-present exogenous Ag on MHC-I but the cellular mechanisms underlying this observation remain unknown. We tested whether primary female mouse aortic ECs could cross-present exogenous male Ag to the T cell hybridoma, MHH, specific for HYUty plus D(b). MHC-I-deficient male spleen cells provided a source of male Ag that could not directly stimulate the MHH cells. Addition of male but not female MHC-I-deficient spleen cells to wild-type syngeneic female EC induced MHH stimulation, demonstrating EC cross-presentation. Lactacystin treatment of the donor male MHC-I-deficient spleen cells, to inhibit proteasome function, markedly enhanced EC cross-presentation showing that the process is most efficient for intact proteins rather than degraded peptide fragments. Additional experiments revealed that this EC Ag-processing pathway is both proteasome and TAP1 dependent. These studies demonstrate that cultured murine aortic ECs can process and present MHC-I-restricted Ag derived from a separate, live cell, and they offer insight into the molecular requirements involved in this EC Ag presentation process. Through this pathway, ECs expressing cross-presented peptides can participate in the effector phase of T cell-mediated inflammatory responses such as autoimmunity, anti-tumor immunity, and transplant rejection.
Bagai
Rakesh
R
Department of Immunology, Cleveland Clinic Foundation, Cleveland, OH 44195, USA.
Valujskikh
Anna
A
Canaday
David H
DH
Bailey
Erin
E
Lalli
Peter N
PN
Harding
Clifford V
CV
Heeger
Peter S
PS
D000071181:ATP Binding Cassette Transporter, Subfamily B, Member 2; D018528:ATP-Binding Cassette Transporters / Q000502:physiology*; D000818:Animals; D017951:Antigen Presentation; D002478:Cells, Cultured; D045142:Cross-Priming / Q000276:immunology*; D004730:Endothelium, Vascular / Q000166:cytology / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism*; D005260:Female; D006182:H-Y Antigen / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D015395:Histocompatibility Antigens Class I / Q000276:immunology / Q000378:metabolism*; D006825:Hybridomas; D007424:Intracellular Fluid / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D015778:Minor Histocompatibility Antigens; D046988:Proteasome Endopeptidase Complex / Q000502:physiology*; D011506:Proteins / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology*
D000071181:ATP Binding Cassette Transporter, Subfamily B, Member 2; D018528:ATP-Binding Cassette Transporters; D006182:H-Y Antigen; D015395:Histocompatibility Antigens Class I; D015778:Minor Histocompatibility Antigens; D011506:Proteins; C486171:Tap1 protein, mouse; C102450:Uty protein, mouse; D046988:Proteasome Endopeptidase Complex