Transient JAK/STAT inhibition by ruxolitinib modulates malaria-specific CD4 ⁺ T cell responses and enhances recall immunity in volunteers experimentally infected with Plasmodium falciparum

JAK/STAT signalling is a key regulator of CD4 ⁺ T cell activation and function, influencing immune responses during infection. Ruxolitinib, a JAK1/2 inhibitor, transiently suppresses JAK/STAT signalling, but its impact on antigen-specific CD4 ⁺ T cell responses in malaria is unknown. In this study, we assessed the effects of ruxolitinib on CD4 ⁺ T cell cytokine signalling and immune responses using a controlled human malaria infection model. Whole blood was stimulated with IFNβ, IL-2, or PMA/Ionomycin, and phosphorylated STAT (pSTAT) expression was analysed. AIM assays and CyTOF were used to examine antigen-specific and memory CD4 ⁺ T cell responses during primary and secondary infections. Ruxolitinib significantly reduced pSTAT1, pSTAT3, and pSTAT5 expression in CD4 ⁺ T cells during treatment but did not impair antigen-specific responses. Instead, it enhanced recall immunity during secondary infection, particularly in AIM ⁺ T follicular helper (Tfh), T helper (Th)1, and type 1 regulatory (Tr1) cell subsets. Furthermore, increased frequencies of circulating Th1 and Tfh cells, but not Tr1 cells correlated with improved parasite control. These findings suggest that transient JAK inhibition modulates immune responses in a manner that could be leveraged as a host-directed therapy for malaria. Further research is needed to explore its potential applications in immune modulation for infectious diseases.