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

Shamael R. Dastagir, Jorge Postigo-Fernandez, Chunliang Xu, James H. Stoeckle, Rebuma Firdessa-Fite, Rémi J. Creusot

Research output: Contribution to journalArticle

4 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)27-38
Number of pages12
JournalMolecular Therapy - Methods and Clinical Development
Volume4
DOIs
StatePublished - Mar 17 2017
Externally publishedYes

Fingerprint

Epitopes
T-Lymphocytes
Antigens
Type 1 Diabetes Mellitus
Endosomes
Regulatory T-Lymphocytes
Stromal Cells
Immunotherapy
Dendritic Cells
Peptides
Therapeutics
Proteins

Keywords

  • antigen presentation
  • antigen targeting
  • dendritic cell
  • diabetogenic
  • epitope
  • mimotope
  • stromal cell
  • T cells
  • tolerance
  • type 1 diabetes

ASJC Scopus subject areas

  • Genetics
  • Molecular Biology
  • Molecular Medicine

Cite this

Efficient Presentation of Multiple Endogenous Epitopes to Both CD4+ and CD8+ Diabetogenic T Cells for Tolerance. / Dastagir, Shamael R.; Postigo-Fernandez, Jorge; Xu, Chunliang; Stoeckle, James H.; Firdessa-Fite, Rebuma; Creusot, Rémi J.

In: Molecular Therapy - Methods and Clinical Development, Vol. 4, 17.03.2017, p. 27-38.

Research output: Contribution to journalArticle

Dastagir, Shamael R. ; Postigo-Fernandez, Jorge ; Xu, Chunliang ; Stoeckle, James H. ; Firdessa-Fite, Rebuma ; Creusot, Rémi J. / Efficient Presentation of Multiple Endogenous Epitopes to Both CD4+ and CD8+ Diabetogenic T Cells for Tolerance. In: Molecular Therapy - Methods and Clinical Development. 2017 ; Vol. 4. pp. 27-38.
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