Interleukin-21 Receptor-Mediated Signals Control Autoreactive T Cell Infiltration in Pancreatic Islets

Abstract

It remains unclear how interleukin-21 receptor (IL-21R) contributes to type 1 diabetes. Here wehave shown that dendritic cells (DCs) in the pancreas required IL-21R not for antigen uptake, but to acquire the chemokine receptor CCR7 and migrate into thedraining lymph node. Consequently, less antigen, major histocompatibility complex (MHC) class II, and CD86 was provided to autoreactive effector cells inIl21r(-/-) mice, impairing CD4(+) Tcell activation, CD40:CD40L interactions, and pancreatic infiltration by autoreactive Tcells. CD40 crosslinking restored defective CD4(+) cell expansion and CD4 independently expanded autoreactive CD8(+) cells, but CD8(+) cells still required CD4(+) cells to reach the pancreas and induce diabetes. Diabetes induction by transferred Tcells required IL-21R-sufficient host antigen-presenting cells. Transferring IL-21R-sufficient DCs broke diabetes resistance in Il21r(-/-) mice. We conclude that IL-21R controls both antigen transport by DCs and the crucial beacon function of CD4(+) cells for autoreactive CD8(+) cells to reach the islets.