Polyfunctional CD4⁺ T Cell Responses to Immunodominant Epitopes Correlate with Disease Activity of Virulent <em>Salmonella</em>

<div><p><em>Salmonella enterica</em> serovars are intracellular bacteria capable of causing typhoid fever and gastroenteritis of significant morbidity and mortality worldwide. Current prophylactic and therapeutic treatment is hampered by the emergence of multidrug-resistant (MDR) strains of <em>Salmonella</em>, and vaccines provide only temporal and partial protection in vaccinees. To develop more effective <em>Salmonella</em> vaccines, it is important to understand the development of protective adaptive immunity to virulent <em>Salmonella</em>. Here we report the identification of novel CD4⁺ T cell peptide epitopes, which are conserved among <em>Salmonella</em> serovars. Immunization of <em>Salmonella</em>-infected mice with these peptide epitopes reduces the burden of <em>Salmonella</em> disease. Furthermore, we show that distinct polyfunctional (interferon-γ⁺, tumor necrosis factor⁺, and interleukin-2⁺) <em>Salmonella</em>-specific CD4⁺ T cell responses develop with respect to magnitude and kinetics. Moreover, we found that CD4⁺ T cell responses against immunodominant epitopes are predictive for active <em>Salmonella</em> disease. Collectively, these data could contribute to improved diagnosis of <em>Salmonella</em>-related diseases and rational design of <em>Salmonella</em> vaccines.</p>