Regulation of Diabetogenic Immunity by IL15-Activated Regulatory CD8 T Cells in Type 1 Diabetes

Regulation of Diabetogenic Immunity by IL15-Activated Regulatory CD8 T Cells in Type 1 Diabetes

Blair T. Stocks, Christopher S. Wilson, Andrew F. Marshall, Emilee M. Hoopes and Daniel J. Moore

J Immunol May 24, 2019, ji1800976; DOI: https://doi.org/10.4049/jimmunol.1800976

Abstract

  • Unchecked collaboration between islet-reactive T and B lymphocytes drives type 1 diabetes (T1D). In the healthy setting, CD8 T regulatory cells (Tregs) terminate ongoing T–B interactions.
  • We determined that specific CD8 Tregs from NOD mice lack suppressive function, representing a previously unreported regulatory cell deficit in this T1D-prone strain. NOD mice possess 11-fold fewer Ly-49+ CD8 Tregs than nonautoimmune mice, a deficiency that worsens as NOD mice age toward diabetes and leaves them unable to regulate CD4 T follicular helper cells. As IL-15 is required for Ly-49+ CD8 Treg development, we determined that NOD macrophages inadequately trans-present IL-15. Despite reduced IL-15 trans-presentation, NOD Ly-49+ CD8 Tregs can effectively transduce IL-15–mediated survival signals when they are provided. Following stimulation with an IL-15/IL-15Ra superagonist complex, Ly-49+ CD8 Tregs expanded robustly and became activated to suppress the Ag-specific Ab response. IL-15/IL-15Ra superagonist complex–activated CD8+CD122+ T cells also delayed diabetes transfer, indicating the presence of an underactivated CD8 T cell subset with regulatory capacity against late stage T1D.
  • We identify a new cellular contribution to anti-islet autoimmunity and demonstrate the correction of this regulatory cell deficit. Infusion of IL-15–activated CD8 Tregs may serve as an innovative cellular therapy for the treatment of T1D.

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