Abnormal T Cell Frequencies, Including Cytomegalovirus-Associated Expansions, Distinguish Seroconverted Subjects at Risk for Type 1 Diabetes

Abstract

We analyzed T cell subsets from cryopreserved PBMC obtained from the TrialNet Pathway to Prevention archives. We compared subjects who had previously seroconverted for one or more autoantibodies with non-seroconverted, autoantibody negative individuals. We observed a reduced frequency of MAIT cells among seroconverted subjects. Seroconverted subjects also possessed decreased frequencies of CCR4-expressing CD4 T cells, including a regulatory-like subset. Interestingly, we found an elevation of CD57+, CD28–, CD127–, CD27– CD8 T cells (SLEC) among seroconverted subjects that was most pronounced among those that progressed to disease. The frequency of these SLEC was strongly correlated with CMV IgG abundance among seroconverted subjects, associated with IA-2 levels, and most elevated among CMV+ seroconverted subjects who progressed to disease. Combined, our data indicate discrete, yet profound T cell alterations are associated with islet autoimmunity among at-risk subjects.

Mucosal-associated invariant T cell alterations during the development of human type 1 diabetes

“…7 Peripheral blood MAIT cell alterations during the progression of type 1 diabetes (T1D). Alterations observed in our study in the paediatric cohort (a) and adult cohort (b) are displayed above the black line and those reported in previous studies [34][35][36] are listed below the black line. E, established (more than 10 days after diagnosis); ND, newly diagnosed (less than 10 days after diagnosis); NP, non-progressor; P, progressor Of the MAIT cell alterations observed here, decreased expression of CD27 and production of IFN-γ have also been reported by others in patients with type 1 diabetes [34,35] ( Fig.…”

“…Also, the study by Harms et al did not detect differences in the frequency of 'MAIT-like' cells in children with type 1 diabetes [34]. A more recent study by the same group reported a decreased MAIT cell frequency in AAb + at-risk individuals, especially in those who did not progress to type 1 diabetes [36], which contrasts with our finding of a decreased frequency of MAIT cells in AAb + at-risk children who progressed to type 1 diabetes. Differences in gating strategy for MAIT cells [34], as well as how stringently the study cohorts have been matched for age and HLA background, may explain some of these discrepancies.…”

“…Consequently, our results suggest a temporal association between circulating MAIT cell alterations and the clinical onset of type 1 diabetes. MAIT ↓ [36] MAIT ↔ [36] MAIT ↓ [35] CCR6 + MAIT ↓ [35] CD25 + MAIT ↑ [35] PD-1 + MAIT ↑ [35] IFN-γ + MAIT ↓ [35] 'MAIT-like' ↔ [34] MAIT ↔ [35] CD27 − 'MAIT-like' ↑ [34] IFN-γ + MAIT ↓ [35] a b Fig. 7 Peripheral blood MAIT cell alterations during the progression of type 1 diabetes (T1D).…”

“…A more recent study observed a markedly reduced frequency of circulating MAIT cells in patients with newly diagnosed type 1 diabetes [35]. One more study suggested that the frequency of circulating MAIT cells was also reduced in AAb + at-risk individuals [36]. Variable alterations in CD25, programmed cell death protein 1 (PD-1), C-C chemokine receptor type (CCR)6 and CD27 surface marker expression, as well as IFN-γ and IL-4 production, by peripheral blood MAIT cells from individuals with type 1 diabetes have also been reported in these studies [34,35].…”

Activation-Induced Cell Death of Mucosal-Associated Invariant T Cells Is Amplified by OX40 in Type 2 Diabetic Patients

“…Studies have indicated that proinflammatory cells such as Th1, Th17, and CTL, which increase in obesity and diabetes, also modulate insulin signaling (3,6). Conversely, a number of antiinflammatory cells, such as Th2 and regulatory T cell (Treg), have been associated with the protection of insulin sensitivity (7).…”