IL-27 Receptor Signaling Regulates Memory CD4⁺ T Cell Populations and Suppresses Rapid Inflammatory Responses during Secondary Malaria Infection

Interleukin-27 (IL-27) is known to control primary CD4⁺ T cell responses during a variety of different infections, but its role in regulating memory CD4⁺ T responses has not been investigated in any model. In this study, we have examined the functional importance of IL-27 receptor (IL-27R) signaling in regulating the formation and maintenance of memory CD4⁺ T cells following malaria infection and in controlling their subsequent reactivation during secondary parasite challenge. We demonstrate that although the primary effector/memory CD4⁺ T cell response was greater in IL-27R-deficient (WSX-1^−/−) mice following Plasmodium berghei NK65 infection than in wild-type (WT) mice, there were no significant differences in the size of the maintained memory CD4+ T population(s) at 20 weeks postinfection in the spleen, liver, or bone marrow of WSX-1^−/− mice compared with WT mice. However, the composition of the memory CD4⁺ T cell pool was slightly altered in WSX-1^−/− mice following clearance of primary malaria infection, with elevated numbers of late effector memory CD4⁺ T cells in the spleen and liver and increased production of IL-2 in the spleen. Crucially, WSX-1^−/− mice displayed significantly enhanced parasite control compared with WT mice following rechallenge with homologous malaria parasites. Improved parasite control in WSX-1^−/− mice during secondary infection was associated with elevated systemic production of multiple inflammatory innate and adaptive cytokines and extremely rapid proliferation of antigen-experienced T cells in the liver. These data are the first to demonstrate that IL-27R signaling plays a role in regulating the magnitude and quality of secondary immune responses during rechallenge infections.