4.4 Article

Efficient Presentation of Multiple Endogenous Epitopes to Both CD4+ and CD8+ Diabetogenic T Cells for Tolerance

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Publisher

CELL PRESS
DOI: 10.1016/j.omtm.2016.12.002

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Funding

  1. JDRF Transition Award [10-2010-790]
  2. NIH [P30 DK063608, T32 DK007271]
  3. Office of the Director, National Institutes of Health [S10RR027050, S10OD020056]
  4. DRC Grant [P30 DK063608]

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Antigen-specific immunotherapy of type 1 diabetes, typically via delivery of a single native beta cell antigen, has had little clinical benefit to date. With increasing evidence that diabetogenic T cells react against multiple beta 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.

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