Autoreactive T effector memory differentiation mirrors β cell function in type 1 diabetes

Abstract

In type 1 diabetes, cytotoxic CD8+ T cells with specificity for β cell autoantigens are found in the pancreatic islets, where they are implicated in the destruction of insulin-secreting β cells. In contrast, the disease relevance of β cell-reactive CD8+ T cells that are detectable in the circulation, and their relationship to β cell function, are not known. Here, we tracked multiple, circulating β cell-reactive CD8+ T cell subsets and measured β cell function longitudinally for 2 years, starting immediately after diagnosis of type 1 diabetes. We found that change in β cell-specific effector memory CD8+ T cells expressing CD57 was positively correlated with C-peptide change in subjects below 12 years of age. Autoreactive CD57+ effector memory CD8+ T cells bore the signature of enhanced effector function (higher expression of granzyme B, killer-specific protein of 37 kDa, and CD16, and reduced expression of CD28) compared with their CD57- counterparts, and network association modeling indicated that the dynamics of β cell-reactive CD57+ effector memory CD8+ T cell subsets were strongly linked. Thus, coordinated changes in circulating β cell-specific CD8+ T cells within the CD57+ effector memory subset calibrate to functional insulin reserve in type 1 diabetes, providing a tool for immune monitoring and a mechanism-based target for immunotherapy.

Autoreactive CD8+ T cell exhaustion distinguishes subjects with slow type 1 diabetes progression

“…We found that the comprehensively defined islet-specific phenotypes, though variable across individuals, did not significantly differ by disease status and, indeed, were also present in HCs. Using established markers of CD8 + T cell differentiation, Yeo et al described a positive correlation between changes in C-peptide and changes in effector memory CD57 + β cell-specific CD8 + T cells among young individuals who were newly diagnosed with T1D, implicating antigen load as a driver of differentiation and peripheral migration of this T cell subset (53). However, the relationship of autoreactive CD8 + T cell function and rate of progression in established T1D remains relatively unexplored.…”

Cell type–specific immune phenotypes predict loss of insulin secretion in new-onset type 1 diabetes

“…While much effort has been focused on immunological differences between T1D patients and healthy controls, or with transitions between stages of T1D (52,53), little information is available about associations between immunological features and rates of C-peptide loss following diagnosis. One notable exception is the recent discovery of a subpopulation of autoreactive CD8 + effector memory T cells in the blood whose levels parallel β cell function, suggesting that these cells are either engaged in or tracking the autoimmune response (54). In addition, using a serum-induced expression assay, Cabrera et al (55) found that an index of immune inflammatory state predicted the rate of C-peptide loss in the first 2 years after diagnosis in a limited set of placebo-treated subjects; this relationship was ablated by CTLA4Ig therapy.…”

T cell-selective deletion of Oct1 protects animals from autoimmune neuroinflammation while maintaining neurotropic pathogen response

“…Those memory cells that are formed are defective in pathogen recall responses [4]. Memory cells are the most prone to making proinflammatory cytokines, and memory or memory-like cells can underlie autoimmunity, even in cases of persistent selfantigen exposure [5][6][7]. These findings, and the strong associations between human polymorphisms in binding sites for Oct1 and predisposition for autoimmune disease including MS [11][12][13][14], suggested a possible role for Oct1 in promoting MS.…”

“…Consequently, CD4 + T cells lacking Oct1 are completely defective in memory recall responses. Memory T cells are highly prone to making proinflammatory cytokines, and memory or memory-like cells can underlie autoimmunity (including T1D), even in cases of persistent selfantigen exposure [5][6][7]. In vitro, Oct1 and its cofactor OCA-B coordinately control a large cohort of critical direct target genes in CD4 + lymphocytes, including Il2, Il21, Stat5a, Ifng, Tbx21 (Tbet), Csf2 (Gmcsf ), Tnfrsf4 (Ox40), Icos, and Ctla4 [4].…”