IL-12 and IFN-I differentially regulate secondary CD4+ T cell responses.

Abstract

Abstract Upon re-exposure to antigen, memory T cells give rise to secondary effector responses that enhance clearance and immune protection. Additionally, secondary activation often boosts the number of memory T cells. Therefore, understanding the parameters that control secondary T cell differentiation and function is critical. We report key roles for IL-12 and Type 1 I IFN (IFN-I) in controlling secondary T cell activation, differentiation and memory formation. While IL-12 was required for the development of secondary effector cells with high functional avidity, as well as the optimal formation of secondary T cell memory, IFN-I inhibited both of these features. Within 24 hours of secondary challenge we observed CD4+ memory T cell-dependent increases in serum IL-12 and IFNγ. While IL-12 neutralization resulted in a predictable reduction of IFNγ, blockade of the IFNα/β receptor (IFNAR) induced significantly higher expression of IL-12, IFNγ and IL-6. The effect was indirect, as rechallenge of WT CD4+ memory T cells in an IFNAR-deficient host resulted in increased functional avidity of secondary effector CD4+ T cells. In contrast, secondary T cell expansion was partly curtailed in these hosts, indicating both stimulatory and inhibitory effects for IFN-I in the setting of secondary challenge. Several immunoregulatory functions for IFN-I have been reported, including induction of IL-10. In support of this, secondary challenge of WT CD4+ memory T cells in IL-10-deficient hosts resulted in enhanced secondary effector function. These findings highlight a key role for IFN-I in regulating secondary CD4+ T cell differentiation and suggest potential therapeutic approaches that preferentially target its immunoregulatory functions.