IL-23 and IL-12 responses in activated human T cells retrovirally transduced with IL-23 receptor variants

Interleukin-23 (IL-23) is a regulator of cellular immune responses involved in controlling infections and autoimmune diseases. Effects of IL-23 on T cells are mediated via a receptor complex consisting of an IL-12R beta 1 and a specific IL-23R chain. The R381Q and P310L variants of the IL-23R were recently reported to be associated with autoimmune diseases, suggesting they have an effect on IL-23R function. To investigate this matter, these variants and a newly identified variant, Y173H, were retrovirally transduced into human T cell blasts and functionally characterized by measuring the IL-23-induced signal transduction pathway (i.e., STAT1, STAT3 and STAT4 phosphorylation), and IFN-gamma and IL-10 production. No differences were detected between the genetic variants and wild-type in the function of the IL-23R-chain. Furthermore, while comparing IFN-gamma and IL-10 production in response to IL-23 and IL-12, we found IL-23 to be a more potent IL-10 inducer, and IL-12 a more potent IFN-gamma inducer. In addition, IL-23 also exerted a minor IL-12-like effect by inducing IL-23R-independent, IL-12R beta 1-dependent STAT4 phosphorylation and IFN-gamma production. In conclusion, the reported association between R381Q and P310L variants of the IL-23R and autoimmune diseases does not depend on differences in functional activity between wild-type and R381Q and P310L variants of the IL-23R. (C) 2008 Elsevier Ltd. All rights reserved.