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Mouse Endothelial Cells Cross-Present Lymphocyte-Derived Antigen on Class I MHC via a TAP1- and Proteasome-Dependent Pathway¹

Rakesh Bagai^*, Anna Valujskikh^*, David H. Canaday, Erin Bailey, Peter N. Lalli^*, Clifford V. Harding and Peter S. Heeger^2,*,

^* Department of Immunology, Cleveland Clinic Foundation, Cleveland OH 44195; and Institute of Pathology, Case Western Reserve University, Cleveland OH 44106

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.

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