Increased expression of OX40 on peripheral CD4⁺/CD8⁺ memory T lymphocytes in the pathogenesis of type 1 diabetes

Autoreactive memory T cells are considered to be a primary contributor to chronic islet inflammation in individuals with type 1 diabetes (T1D). OX40-expressing T cells not only facilitate and sustain the presence of CD4⁺ memory T cells but also promote the generation of CD8⁺ memory T cells. We aimed to investigate the role of OX40⁺CD4⁺/CD8⁺ memory T lymphocytes in the pathogenesis of T1D.

A total of 35 patients diagnosed with Type 1 diabetes and 40 healthy control individuals were enrolled in this study. Peripheral Blood Mononuclear Cells (PBMCs) were isolated from the study participants and analyzed by flow cytometry. Inflammatory cytokines in the plasma were quantitatively measured. The pancreatic islet autoantibodies as well as islet function were also evaluated.

The frequencies and the mean fluorescence intensity (MFI) of OX40 on CD4⁺  effector memory T (Tem) cells significantly increased in patients with T1D compared to healthy controls. Importantly, the expression of OX40 on CD8⁺ Tem and central memory T (Tcm) cells was also significantly higher in T1D compared with healthy controls. However, the expression of OX40 on CD4⁺ Tem cells was not significantly higher in T1D with two or more autoantibodies than control group. Furthermore, the frequencies of OX40⁺CD8⁺ Tem cells significantly increased in T1D patients with two or more autoantibodies but not in those with one autoantibody, compared with control groups. Meanwhile, the frequencies of OX40⁺CD8⁺ Tcm cells were consistently higher across all three subgroups of T1D patients (AAb^-, 1AAb, ≥2AAb) compared to the control group. Notably, both the frequencies of OX40⁺CD4⁺ and OX40⁺CD8⁺ Tem cells exhibited significant negative correlations with the serum C-peptide levels in T1D patients. Additionally, the expression levels of OX40 on peripheral CD4⁺/CD8⁺ memory T cells were positively correlated with the levels of plasma inflammatory cytokines in patients with T1D.

The elevated expression of OX40 on CD4⁺/CD8⁺ memory T cells was associated with the autoimmune-mediated destruction of islet beta cells in T1D. Our findings indicate that the expression levels of OX40 on peripheral CD4⁺ and CD8⁺ memory T lymphocytes may serve as potential predictive biomarkers for the severity of T1D. Additionally, OX40 expression on memory T cells may serve as a potential biomarker for assessing the efficacy of immunotherapy in T1D patients.