Interleukin-21 receptor-mediated signals control autoreactive T cell infiltration in pancreatic islets

Immunity. 2012 Jun 29;36(6):1060-72. doi: 10.1016/j.immuni.2012.04.005. Epub 2012 May 10.

Abstract

It remains unclear how interleukin-21 receptor (IL-21R) contributes to type 1 diabetes. Here we have 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 the draining lymph node. Consequently, less antigen, major histocompatibility complex (MHC) class II, and CD86 was provided to autoreactive effector cells in Il21r(-/-) mice, impairing CD4(+) T cell activation, CD40:CD40L interactions, and pancreatic infiltration by autoreactive T cells. 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 T cells 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adoptive Transfer
  • Animals
  • Antigen Presentation
  • Autoimmunity / immunology*
  • CD4-Positive T-Lymphocytes / immunology
  • CD40 Antigens / immunology
  • CD40 Ligand / immunology
  • CD8-Positive T-Lymphocytes / immunology
  • Chemotaxis, Leukocyte
  • Diabetes Mellitus, Type 1 / immunology*
  • Diabetes Mellitus, Type 1 / pathology
  • Disease Models, Animal
  • Disease Resistance
  • Interleukin-21 Receptor alpha Subunit / deficiency
  • Interleukin-21 Receptor alpha Subunit / genetics
  • Interleukin-21 Receptor alpha Subunit / physiology*
  • Islets of Langerhans / immunology*
  • Lymph Nodes / immunology
  • Lymph Nodes / pathology
  • Lymphocyte Activation
  • Lymphocyte Cooperation
  • Lymphocytic choriomeningitis virus
  • Mice
  • Mice, Inbred NOD
  • Receptors, CCR7 / metabolism
  • Specific Pathogen-Free Organisms
  • Spleen / immunology
  • T-Lymphocyte Subsets / immunology*
  • T-Lymphocyte Subsets / transplantation

Substances

  • CD40 Antigens
  • Ccr7 protein, mouse
  • Il21r protein, mouse
  • Interleukin-21 Receptor alpha Subunit
  • Receptors, CCR7
  • CD40 Ligand