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

Stocks BT, Wilson CS, Marshall AF, Hoopes EM, Moore DJ
J Immunol. 2019 203 (1): 158-166

PMID: 31127035 · PMCID: PMC6581590 · DOI:10.4049/jimmunol.1800976

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 -present IL-15. Despite reduced IL-15 -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 CD8CD122 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.

Copyright © 2019 by The American Association of Immunologists, Inc.

MeSH Terms (15)

Adoptive Transfer Animals B-Lymphocytes CD8 Antigens Cells, Cultured Diabetes Mellitus, Type 1 Disease Models, Animal Humans Immunotherapy, Adoptive Interleukin-15 Macrophages Mice Mice, Inbred NOD NK Cell Lectin-Like Receptor Subfamily A T-Lymphocytes, Regulatory

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