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Regulation of Diabetogenic Immunity by IL-15-Activated Regulatory CD8 T Cells in Type 1 Diabetes.


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.

SUBMITTER: Stocks BT 

PROVIDER: S-EPMC6581590 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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Regulation of Diabetogenic Immunity by IL-15-Activated Regulatory CD8 T Cells in Type 1 Diabetes.

Stocks Blair T BT   Wilson Christopher S CS   Marshall Andrew F AF   Hoopes Emilee M EM   Moore Daniel J DJ  

Journal of immunology (Baltimore, Md. : 1950) 20190524 1


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<sup>+</sup> CD8 Tregs than nonautoimmune mice, a deficiency that worsens as NOD mice age toward diabetes and  ...[more]

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