title: Efficient Presentation of Multiple Endogenous Epitopes to Both CD4+and CD8+Diabetogenic T Cells for Tolerance.
abstract: Antigen-specific immunotherapy of type 1 diabetes, typically via delivery of a single native β cell antigen, has had little clinical benefit to date. With increasing evidence that diabetogenic T cells react against multiple β cell antigens, including previously unappreciated neo-antigens that can be emulated by mimotopes, a shift from protein- to epitope-based therapy is warranted. To this end, we aimed to achieve efficient co-presentation of multiple major epitopes targeting both CD4+and CD8+diabetogenic T cells. We have compared native epitopes versus mimotopes as well as various targeting signals in an effort to optimize recognition by both types of T cells in vitro. Optimal engagement of all T cells was achieved with segregation of CD8 and CD4 epitopes, the latter containing mimotopes and driven by endosome-targeting signals, after delivery into either dendritic or stromal cells. The CD4+T cell responses elicited by the endogenously delivered epitopes were comparable with high concentrations of soluble peptide and included functional regulatory T cells. This work has important implications for the improvement of antigen-specific therapies using an epitope-based approach to restore tolerance in type 1 diabetes and in a variety of other diseases requiring concomitant targeting of CD4+and CD8+T cells.
authors.affiliation: Columbia Center for Translational Immunology and Department of Medicine, Columbia University Medical Center, New York, NY 10032, USA.
authors.forename: Shamael R
authors.initials: SR
authors.lastname: Dastagir
authors.affiliation: Columbia Center for Translational Immunology and Department of Medicine, Columbia University Medical Center, New York, NY 10032, USA.
authors.forename: Jorge
authors.initials: J
authors.lastname: Postigo-Fernandez
authors.affiliation: Columbia Center for Translational Immunology and Department of Medicine, Columbia University Medical Center, New York, NY 10032, USA.
authors.forename: Chunliang
authors.initials: C
authors.lastname: Xu
authors.affiliation: Columbia Center for Translational Immunology and Department of Medicine, Columbia University Medical Center, New York, NY 10032, USA.
authors.forename: James H
authors.initials: JH
authors.lastname: Stoeckle
authors.affiliation: Columbia Center for Translational Immunology and Department of Medicine, Columbia University Medical Center, New York, NY 10032, USA.
authors.forename: Rebuma
authors.initials: R
authors.lastname: Firdessa-Fite
authors.affiliation: Columbia Center for Translational Immunology and Department of Medicine, Columbia University Medical Center, New York, NY 10032, USA.
authors.forename: Rémi J
authors.initials: RJ
authors.lastname: Creusot
keywords: T cells; antigen presentation; antigen targeting; dendritic cell; diabetogenic; epitope; mimotope; stromal cell; tolerance; type 1 diabetes