Insulin-like growth factors are essential for the differentiation of Th17s in EAE (LYM8P.635)

Abstract

Abstract Insulin-like growth factors (Igfs) are highly conserved proteins similar to pro-insulin in both sequence and structure. They function primarily by binding the Igf1 receptor (Igf1R) and exert pleiotropic effects on many tissues throughout life. These factors were shown to be essential for the normal development and proliferation of B and T lymphocytes, and to positively influence their proliferation and survival following activation. But early attempts to identify potential roles in T cell differentiation and function lead to conflicting results, and the field was largely abandoned. More recent advances in our understanding of T cell biology, however, including the discovery of Th17 and Treg C4s, have permitted a more sophisticated analysis of the role of this system in T cells. Our data indicate that Th17 and Treg CD4s express Igf1R and insulin-like growth factor binding protein 4 (Igfbp4), a critical regulator of Igf activity, at much higher levels than other CD4 T cells, and appear uniquely capable of responding to Igfs. Exogenous Igfs promote Th17 and suppress Treg differentiation in-vitro, yet fail to influence Th1 or Th2 differentiation. Deletion of Igf1R leads to a defect in Stat3 phosphorylation and IL17a production, and enhanced Treg differentiation in-vitro. Mice lacking Igf1R on T cells are substantially protected from Experimental Autoimmune Encephalomyelitis, an effect that can be recapitulated through the in-vivo administration of Igf1R blocking antibodies.