title: CD13 regulates dendritic cell cross-presentation and T cell responses by inhibiting receptor-mediated antigen uptake.
abstract: Dendritic cell (DC) Ag cross-presentation is generally associated with immune responses to tumors and viral Ags, and enhancement of this process is a focus of tumor vaccine design. In this study, we found that the myeloid cell surface peptidase CD13 is highly and specifically expressed on the subset of DCs responsible for cross-presentation, the CD8(+) murine splenic DCs. In vivo studies indicated that lack of CD13 significantly enhanced T cell responses to soluble OVA Ag, although development, maturation, and Ag processing and presentation of DCs are normal in CD13KO mice. In vitro studies showed that CD13 regulates receptor-mediated, dynamin-dependent endocytosis of Ags such as OVA and transferrin but not fluid-phase or phagocytic Ag uptake. CD13 and Ag are cointernalized in DCs, but CD13 did not coimmunoprecipitate with Ag receptors, suggesting that CD13 does not control internalization of specific receptors but regulates endocytosis at a more universal level. Mechanistically, we found that phosphorylation of the endocytic regulators p38MAPK and Akt was dysregulated in CD13KO DCs, and blocking of these kinases perturbed CD13-dependent endocytic uptake. Therefore, CD13 is a novel endocytic regulator that may be exploited to enhance Ag uptake and T cell activation to improve the efficacy of tumor-targeted vaccines.
authors.affiliation: University of Connecticut Health Center, Farmington, CT 06030, USA.
authors.forename: Mallika
authors.initials: M
authors.lastname: Ghosh
authors.forename: Beata
authors.initials: B
authors.lastname: McAuliffe
authors.forename: Jaganathan
authors.initials: J
authors.lastname: Subramani
authors.forename: Sreyashi
authors.initials: S
authors.lastname: Basu
authors.forename: Linda H
authors.initials: LH
authors.lastname: Shapiro
mesh_terms: D000818:Animals; D000941:Antigens / Q000378:metabolism*; D018826:CD13 Antigens / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D016827:CD8 Antigens / Q000096:biosynthesis; D045142:Cross-Priming / Q000235:genetics / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism; D015536:Down-Regulation / Q000276:immunology*; D006801:Humans; D007108:Immune Tolerance / Q000235:genetics; D037181:Lectins, C-Type / Q000037:antagonists & inhibitors / Q000502:physiology; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins / Q000037:antagonists & inhibitors / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D011956:Receptors, Cell Surface / Q000037:antagonists & inhibitors / Q000502:physiology; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism
chemical_list: D000941:Antigens; D016827:CD8 Antigens; D037181:Lectins, C-Type; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins; D011956:Receptors, Cell Surface; D018826:CD13 Antigens