EBV-induced gene B augments IL-23R[alpha] protein expression through a chaperone calnexin

Introduction Cytokines of the IL-12 family play critical roles in regulating the differentiation of Th cells and their effector functions (1). These cytokines are composed of 2 distinct subunits forming [...]
Epstein-Barr virus-induced gene 3 (EBI3) is a subunit commonto IL-27, IL-35, and IL-39. Here, we explore an intracellular role of EBI3 that is independent of its function In cytokines. EBI3-deflclent naive [CD4.sup.+] T cells had reduced IFN-[gamma] production and failed to induce T cell-dependent colitis in mice. Similarly reduced IFN-[gamma] production was observed In vitro in EBI3-deficient [CD4.sup.+] T cells differentiated under pathogenic Th17 polarizing conditions with IL-23. This is because the induction of expression of one of the IL-23 receptor (IL-23R) subunits, IL-23R[alpha], but not another IL-23R subunit, IL-12R[beta]1, was selectively decreased at the protein level, but not the mRNA level. EBI3 augmented IL-23R[alpha] expression via bindingto the chaperone molecule calnexin and to IL-23R[alpha] in a peptide-dependent manner, but not a glycan-dependent manner. Indeed, EBI3 failed to augment IL-23R[alpha] expression in the absence of endogenous calnexin. Moreover, EBI3 poorly augmented the expression of C149R, an IL-23R[alpha] variant that protects against the development of human colitis, because binding of EBI3 to the variant was reduced. Taken together with the result that EBI3 expression Is Inducible InT cells, the present results suggest that EBI3 plays a critical role in augmenting IL-23R[alpha] protein expression via calnexin under inflammatory conditions.