Programmed death-1 restrains the germinal center reaction in type 1 diabetes

Abstract

Abstract Programmed death-1 (PD-1) is a T cell inhibitory receptor important for tolerance maintenance. PD-1 deficiency or blockade accelerates autoimmune diabetes in non-obese diabetic (NOD) mice, but the mechanism remains unclear. Autoantibody production is a hallmark of autoimmunity, and has also been reported in patients treated with PD-1 blockade, suggesting that PD-1 might regulate this process. Autoantibody production results from B cell:CD4 T cell interactions in the germinal center of the lymph node. The dynamics and regulation of the germinal center response in spontaneous autoimmunity and in the face of PD-1 deprivation are not well understood, primarily due to an inability to track self-specific lymphocytes. To bridge this knowledge gap, we used tetramers to phenotype islet-specific CD4 T cells and B cells in mice. PD-1-deficient mice, and NOD mice treated with anti-PD-1, had increased insulin autoantibodies, as well as increased insulin-specific germinal center T follicular helper CD4 T cells and germinal center B cells compared to controls. This work provides a mechanistic explanation for autoantibody onset following PD-1 blockade in the clinic, and has important implications for cancer immunotherapy and autoimmunity.