Temporal Alterations in CD8⁺ T Cells During the Progression from Stage 1 to Stage 3 Type 1 Diabetes

Version 2 2024-08-29, 14:37

Version 1 2024-07-05, 16:02

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posted on 2024-08-29, 14:37 authored by Anna-Mari Schroderus, Viola Pitkänen, Ilse Ekman, Daniella Stevens, Marja A. Rytkönen-Nissinen, Reeta Rintamäki, Jussi Pihlajamäki, Mikael Knip, Riitta Veijola, Jorma Toppari, Jorma Ilonen, Johanna Lempainen, Tuure Kinnunen

ABSTRACT

CD8⁺ T cells are perceived to play a major role in the pathogenesis of type 1 diabetes (T1D). In this study, we characterized the function and phenotype of circulating CD8⁺ memory T cells in samples from individuals at different stages of T1D progression using flow cytometry and single-cell multiomics. We observed two distinct CD8⁺ T-cell signatures during progression of T1D within the highly differentiated CD27^-CD8⁺ memory T cell subset. A proinflammatory signature, with an increased frequency of IFN-γ⁺TNF-α⁺ CD27^-CD8⁺ memory T cells, was observed in children with newly diagnosed T1D (stage 3) and correlated with the level of dysglycemia at diagnosis. In contrast, a co-inhibitory signature, with an increased frequency of KLRG1⁺TIGIT⁺CD27^-CD8⁺ memory T cells, was observed in islet autoantibody-positive children who later progressed to T1D (stage 1). No alterations within CD27^-CD8⁺ memory T cells were observed in adults with established T1D or in children during the initial seroconversion to islet autoantibody positivity. Single-cell multiomics analyses suggested that CD27^-CD8⁺ T cells expressing the IFNG⁺TNF⁺ proinflammatory signature may be distinct from those expressing the KLRG1⁺TIGIT⁺ co-inhibitory signature at the single-cell level. Collectively, our findings suggest that distinct blood CD8⁺ T-cell signatures could be employed as potential biomarkers of T1D progression.

Keywords: type 1 diabetes, autoimmunity, T cells, human, CD8⁺ T cells, single-cell multiomics

ARTICLE HIGHLIGHTS

· Blood CD8⁺ T-cell signatures have recently been associated with a slower progression of T1D after diagnosis and with clinical response to immunotherapy.

· We investigated blood CD8⁺ T-cell signatures in individuals at different stages of T1D progression.

· We observed two distinct CD8⁺ T-cell signatures at different stages of T1D: a proinflammatory signature in children with newly diagnosed T1D (stage 3) and a co-inhibitory signature in autoantibody-positive children who later progressed to T1D (stage 1).

· CD8⁺ T-cell signatures could potentially be utilized as biomarkers for evaluating the risk of T1D progression.