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.

CD8+ Regulatory T Cell – A Mystery to Be Revealed

“…In addition to abovementioned EAE model (19,36,37), CD8 + CD122 hi Ly49 + Tregs have documented functions in various settings, including colitis (38,39), hepatitis (40), arthritis (41), diabetes (42,43), viral infection (44), tumor immunity (45), atherogenesis (46) and organ transplantation (47). The best demonstrated role of CD8 + Tregs is to suppress GC reaction.…”

CD8+ Tregs revisited: A heterogeneous population with different phenotypes and properties

“…Despite these initial reports, it became clear that CD122 is not suitable as a standalone marker for mouse and human CD8 + Treg cells, as it is upregulated in memory‐phenotype and antigen‐experienced cells [38–42]. For these reasons, some researchers proposed additional or alternative markers of the CD8 + CD122 + population such as CD44 [43, 44], CD62L [44], CXCR3 [38], PD‐1 [44, 45], CD38 [46], and Ly49 [43, 47, 48]. It is also clear that CD8 + CD122 + T cells overlap, at least partially, with antigen inexperienced memory‐like T (AIMT) cells (alias virtual memory T cells), that is, CD8 + T cells that have memory phenotype despite no previous antigen exposure [42, 49, 50].…”

“…The regulatory capacities of CD8 + CD122 + T cells have been documented in models of experimental colitis, experimental autoimmune encephalomyelitis (EAE) and autoimmune diabetes [48, 51, 52]. These experiments showed that CD8 + CD122 + T cells are able to prevent the development of an autoimmune disease or ameliorate its symptoms, but did not fully enlighten the underlying mechanisms.…”

Cytokines in type 1 diabetes: mechanisms of action and immunotherapeutic targets

“…93 This finding led to the treatment of NOD mice with adoptively transferred IL-15-activated CD8 + Tregs, which resulted in delayed diabetes onset. 93 Notably, IL-15-mediated Foxp3 expression in CD4 + Tregs could be abrogated by IL-15-activated NK cells. 92 The results of these studies show that IL-15 can accelerate T1D in vivo and, more importantly, also regulates diabetogenic effects via activation of Tregs, which, however, may be eliminated by simultaneous activation of diabetogenic T cells and NK cells.…”

“…IL‐15 is required for the development of Ly49 + CD8 + Tregs, whose deficiency is increased with ageing, as NOD mice progress towards diabetes (Figure 1 and Table 1). This finding led to the treatment of NOD mice with adoptively transferred IL‐15‐activated CD8 + Tregs, which resulted in delayed diabetes onset . Notably, IL‐15‐mediated Foxp3 expression in CD4 + Tregs could be abrogated by IL‐15‐activated NK cells .…”