T-Bet Modulates Plasmodium-Specific CD4⁺ T Cell Differentiation and Anti-Malarial Immunity During Blood-Stage...

CD4⁺ T helper (Th)1 cells are theorized to control Plasmodium parasite burden during blood-stage malaria. However, their exact role in controlling parasitemia in vivo remains inadequately characterized. Here, we used a CD4⁺ T cell-restricted Cre-Lox T-bet (the master regulator of Th1 cells) excision mouse model to examine the role of Plasmodium-specific Th1 cell responses in controlling blood-stage infection. Our results found that T-bet deficiency in CD4⁺ T cells markedly enhanced the growth of blood-stage Plasmodium yoelii (P. yoelii) 17XNL and Plasmodium chabaudi (P. chabaudi) AS, but not Plasmodium berghei (P. berghei) ANKA. Although T-bet deficiency in CD4⁺ T cells did not significantly impair the generation of pathogen-specific GC-Tfh cells, GC B cells, or the production of Plasmodium-specific antibodies, it profoundly suppressed Plasmodium-specific Th1 differentiation and IFN-γ production. Conversely, T-bet deficiency selectively promoted Plasmodium-specific Th17 differentiation without affecting other Th subsets. However, despite the heightened Th17 cell responses, in vivo neutralization of IL-17A did not impact host defence against P. yoelii 17XNL infection. Collectively, our data demonstrate that T-bet in CD4⁺ T cells enhances Plasmodium-specific Th1 cell responses while restraining Plasmodium-specific Th17 cell differentiation. In addition, Plasmodium-specific Th1 cells can confer substantial protection against blood-stage malaria. These findings support the development of effective malaria vaccines designed to elicit robust CD4⁺ Th1 responses.