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Aims: 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. Methods: 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. Results: Frequencies of PD-1+ CD8+ Tem cells were decreased significantly in PBMC of patients with T1D (40.73 ± 12.72 vs 47.43 ± 15.56, *p < 0.05). 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 ± 12.72%, *p < 0.05). 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 (≥ 2AAb vs HC 33.1 ± 8.92% vs 43.71 ± 11.78%, *p < 0.05; ≥ 2AAb vs AAb—33.1 ± 8.92% vs 41.65 ± 11.2%, *p < 0.05; ≥ 2AAb vs 1AAb 33.1 ± 8.92% vs 48.09 ± 10.58%, ***p < 0.001). The frequencies of PD-1+CD8+ Tem cells were positively correlated with fasting serum C-peptide levels (r = 0.4308, *p < 0.05) and C-peptide levels 2 h after meal in T1D patients (r = 0.5723, **p < 0.01). The frequencies of PD-1+CD8+ Tcm cells were only negatively correlated with the levels of HbA1c (r = − 0.2992, *p < 0.05). 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 ± 6.455% vs 27.69 ± 9.837%, *p < 0.05). Pathologically, CD8, PD-1 and PD-L1 were strongly expressed in the islets of diabetic mice after PD-1 blockade. Conclusions: 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. [ABSTRACT FROM AUTHOR]

Summary: B7‐H4, one of the immunoregulatory proteins, plays an inhibitory role by inhibiting T cell proliferation and cytokine production. Nevertheless, the significance of soluble B7‐H4 (sB7‐H4) in autoimmune diseases is unclear. In our study, we developed two novel mouse anti‐human B7‐H4 monoclonal antibodies (mAbs) (clones 8D4 and 7E1) with utilities for flow cytometry, immunoblotting and immunofluorescence. We characterized 7E1 as a functional antibody with antagonistic activity, which could promote T cell proliferation and regulate cytokine production. Furthermore, based on the different epitope specificities, we established a novel enzyme‐linked immunosorbent assay (ELISA) which could detect sB7‐H4 sensitively and specifically. Using this ELISA kit, sB7‐H4 was observed in a high proportion of autoimmune diseases patients. We found that the levels of sB7‐H4 were significantly higher in patients with systemic lupus erythematosus (SLE), type I diabetes (T1D) and Graves' disease (GD). Together, sB7‐H4 in human serum is regarded not only as a regulator of T cell activation but may also be a diagnostic marker of autoimmune diseases. [ABSTRACT FROM AUTHOR]

This study analyzed the expression of membrane OX40 and OX40L (mOX40 and mOX40L) and levels of soluble OX40 and OX40L (sOX40 and sOX40L) in T1D patients to determine their clinical significance. Peripheral blood (PB) was collected from patients with T1D and healthy control participants. Expression of mOX40 and mOX40L on immune cells was detected by flow cytometry. Levels of sOX40 and sOX40L in sera were measured by ELISA. We demonstrated for the first time enhanced sOX40 and sOX40L expression and reduced mOX40 and mOX40L levels in T1D patients which correlated with the clinical characteristics and inflammatory factors. These results suggest that OX40/OX40L signal may be promising biomarkers and associated with the pathogenesis of T1D. [ABSTRACT FROM AUTHOR]

Type 1 Diabetes (T1D) is an autoimmune disease resulting from insulin-secreting β-cells mediated by autoreactive T cells. We demonstrated increased level of sB7-H3 in T1D patients than in healthy control group. This result suggests that B7-H3 may be may be a promising biomarker associated with the pathogenesis of T1D. [ABSTRACT FROM AUTHOR]