High common-γ cytokine receptor levels promote expression of Interleukin-2/Interleukin-7 receptor α-chains with implications on T-cell differentiation and function

Abstract

Cytokines of the common-γ receptor chain (γ_c) family are crucial for T-cell differentiation and dysregulation of γ_c cytokine pathways is involved in the pathogenesis of autoimmune diseases. There is increasing evidence that the availability of the γ_c receptor (CD132) for the associated receptor chains has implications for T-cell functions. Here we studied the influence of differential γ_c expression on the expression of the IL-2Rα (CD25), the IL-7Rα (CD127) and the differentiation of activated naïve T cells. We fine-tuned the regulation of γ_c expression in human primary naïve T cells by lentiviral transduction using small hairpin (sh)RNAs and γ_c cDNA. Differential γ_c levels were then analysed for effects on T-cell phenotype and function after activation. Differential γ_c expression markedly affected IL-2Rα and IL-7Rα expression on activated naïve T cells. High γ_c expression (γ_c-high) induced significantly higher expression of IL-2Rα and re-expression of IL-7Rα after activation. Inhibition of γ_c caused lower IL-2Rα/IL-7Rα expression and impaired proliferation of activated naïve T cells. In contrast, γ_c-high T cells secreted significantly higher concentrations of effector cytokines (i.e., IFN-γ, IL-6) and showed higher cytokine-receptor induced STAT5 phosphorylation during initial stages as well as persistently higher pSTAT1 and pSTAT3 levels after activation. Finally, accelerated transition towards a CD45RO expressing effector/memory phenotype was seen especially for CD4⁺ γ_c-high naïve T cells. These results suggested that high expression of γ_c promotes expression of IL-2Rα and IL-7Rα on activated naïve T cells with significant effects on differentiation and effector cytokine expression.