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

ABSTRACT

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.