Invariant chain and the MHC class II cytoplasmic domains regulate localization of MHC class II molecules to lipid rafts in tumor cell-based vaccines.

TitleInvariant chain and the MHC class II cytoplasmic domains regulate localization of MHC class II molecules to lipid rafts in tumor cell-based vaccines.
Publication TypeJournal Article
Year of Publication2004
AuthorsDolan BP, Phelan TP, Ilkovitch D, Qi L, Wade WF, Laufer TM, Ostrand-Rosenberg S
JournalJournal of immunology (Baltimore, Md. : 1950)
Volume172
Issue2
Pagination907-14
Date Published2004 Jan 15
ISSN0022-1767
KeywordsAdjuvants, Immunologic, Animals, Antigen Presentation, Antigen-Presenting Cells, Antigens, Differentiation, B-Lymphocyte, Cancer Vaccines, Cell Line, Tumor, Cytoplasm, Down-Regulation, Histocompatibility Antigens Class II, Lymphoma, B-Cell, Membrane Microdomains, Mice, Mice, Inbred A, Mice, Inbred BALB C, Protein Structure, Tertiary, Sarcoma, Sequence Deletion, Transfection
Abstract

Cell-based tumor vaccines, consisting of MHC class I+ tumor cells engineered to express MHC class II molecules, stimulate tumor-specific CD4+ T cells to mediate rejection of established, poorly immunogenic tumors. Previous experiments have demonstrated that these vaccines induce immunity by functioning as APCs for endogenously synthesized, tumor-encoded Ags. However, coexpression of the MHC class II accessory molecule invariant chain (Ii), or deletion of the MHC class II cytoplasmic domain abrogates vaccine immunogenicity. Recent reports have highlighted the role of lipid microdomains in Ag presentation. To determine whether Ii expression and/or truncation of MHC class II molecules impact vaccine efficacy by altering MHC class II localization to lipid microdomains, we examined the lipid raft affinity of MHC class II molecules in mouse M12.C3 B cell lymphomas and SaI/A(k) sarcoma vaccine cells. Functional MHC class II heterodimers were detected in lipid rafts of both cell types. Interestingly, expression of Ii in M12.C3 cells or SaI/A(k) cells blocked the MHC class II interactions with cell surface lipid rafts. In both cell types, truncation of either the alpha- or beta-chain decreased the affinity of class II molecules for lipid rafts. Simultaneous deletion of both cytoplasmic domains further reduced localization of class II molecules to lipid rafts. Collectively, these data suggest that coexpression of Ii or deletion of the cytoplasmic domains of MHC class II molecules may reduce vaccine efficacy by blocking the constitutive association of MHC class II molecules with plasma membrane lipid rafts.

Alternate JournalJ. Immunol.