CD4⁺ T cell protection against murine Salmonella infection is female-specific and estrogen-dependent

CD4⁺ T cells are necessary to control intracellular bacterial infections, but the role of sex in these infections is poorly understood. Here we show that upon challenge with Salmonella, a model intracellular bacterium, more male mice succumb to infection than females, despite having more Salmonella specific CD4⁺ T cells at later infection stages. Upon infecting mice lacking CD4⁺ T cells, survival differences reverse, which suggests that female and male CD4⁺ T cells play opposing roles during infection. Transfer of purified CD4⁺ T cells from either sex into CD4 deficient mice restores survival in females but decreases survival in males. Decreasing the hormone 17β-estradiol in females induces a more severe male-like phenotype. Exogenous 17β-estradiol induces both inflammatory and suppressive cytokines in CD4⁺ T cells from infected female mice and restores the protective function of T cells during infection. These findings reveal a sex difference in CD4⁺ T cell behavior during intracellular bacterial infection.