Decreased expression of programmed death-1 on CD8+ effector memory T lymphocytes correlates with the pathogenesis of type 1 diabetes

Abstract

Chronic inflammation of autoimmune diseases, including type 1 diabetes (T1D), is mainly mediated by memory T(Tm) cells, predominantly effector memory T (Tem) cells. The roles of the programmed death-1 (PD-1) receptor on lymphocytes have been well studied in tumor and other infection models. However, little is known about the relationship between the expression of PD-1 on CD8+ Tem cells and the pathogenesis of T1D. A total of 52 patients diagnosed with T1D and 39 gender-, age-, and ethnically matched health control individuals were enrolled in this study. Peripheral blood mononuclear cells from these individuals were isolated and analyzed by flow cytometry. We evaluated the frequencies of PD-1+ CD8+ memory T cell subsets from patients peripheral blood with T1D and the spleen cells of nonobese diabetic (NOD) mice in the present study. We also investigated the effects of blocking PD-1/PD-L1 pathway on islet’s inflammation in NOD mice. Frequencies of PD-1+ CD8+ Tem cells were decreased significantly in PBMC of patients with T1D (40.73\u2009±\u200912.72 vs 47.43\u2009±\u200915.56, *p\u2009<\u20090.05). The frequencies of PD-1+ CD8+ Tem cells were decreased in patients with T1D who were positive for two or more autoantibodies compared with the patients with one autoantibody (13.46% vs 46.95\u2009±\u200912.72%, *p\u2009<\u20090.05). Meanwhile, the frequencies of PD-1+ CD8+ central memory T (Tcm) cells were also significantly decreased in patients with two or more autoantibodies compared with other groups (≥\u20092AAb vs HC 33.1\u2009±\u20098.92% vs 43.71\u2009±\u200911.78%, *p\u2009<\u20090.05;\u2009≥\u20092AAb vs AAb—33.1\u2009±\u20098.92% vs 41.65\u2009±\u200911.2%, *p\u2009<\u20090.05; ≥\u20092AAb vs 1AAb 33.1\u2009±\u20098.92% vs 48.09\u2009±\u200910.58%, ***p\u2009<\u20090.001). The frequencies of PD-1+CD8+ Tem cells were positively correlated with fasting serum C-peptide levels (r\u2009=\u20090.4308, *p\u2009<\u20090.05) and C-peptide levels 2 h after meal in T1D patients (r\u2009=\u20090.5723, **p\u2009<\u20090.01). The frequencies of PD-1+CD8+ Tcm cells were only negatively correlated with the levels of HbA1c (r\u2009=\u2009− 0.2992, *p\u2009<\u20090.05). Similarly, the frequencies of PD-1+CD8+ Tem were significantly decreased in intervention group (anti-mouse PD-1 mAb) compared with the control group (14.22\u2009±\u20096.455% vs 27.69\u2009±\u20099.837%, *p\u2009<\u20090.05). Pathologically, CD8, PD-1 and PD-L1 were strongly expressed in the islets of diabetic mice after PD-1 blockade. It is the first report of the expression of PD-1 on CD8+ Tem cells in T1D in the present study. Our observations suggest that the PD-1/PD-L1 signal pathway on CD8+ Tem cells of T1D subjects might identify a new pathway for delaying the occurrence and development by inhibiting autoimmunity.