IL21 is a critical regulator of chronic/persistent auto-immune and allo-immune responses (P5162)

Abstract

Abstract IL21 is critical for T1D development in NOD mice, but its role in sustaining T cell responses against islets during T1D progression remains unexplored. Our studies show that diabetic NOD mice have high levels of serum IL21. We thus hypothesized that IL21 produced by activated CD4 T cells in spontaneously diabetic NOD mice sustains T cell responses to islets. Indeed, IL21 is required for maintaining the function of auto-reactive immune cells during T1D progression as transient therapy with IL21 receptor fusion protein (IL21RFc) was effective in reversing the onset of T1D in NOD mice (n=11) and inducing long-term T1D remission for up to 20 weeks in at least 3 mice. Pancreatic infiltrates of IL21RFc-treated NOD mice contain mostly CD4 T cells that lost surface ICOS expression while containing fewer CD8 T cells, suggesting that IL21RFc inhibited CD4 T cell help to CD8 T cells. In a parallel study, we have shown that IL21 deficient mice were protected from chronic allograft vasculopathy in a MHC class-II mismatched cardiac allograft model. However, IL21 deficient mice acutely rejected fully mismatched cardiac allografts similar to wild type. Thus, we have demonstrated a novel and critical role for IL21 signaling in driving chronic immune responses against auto and allo-antigens. Based on our findings, IL21 has the potential to act as a serum biomarker for early T1D detection and a therapeutic target to abrogate persistent T cell responses in T1D and chronic allograft rejection.