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

Salmonella enterica 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 Salmonella, and vaccines provide only temporal and partial protection in vaccinees. To develop more effective Salmonella vaccines, it is important to understand the development of protective adaptive immunity to virulent Salmonella. Here we report the identification of novel CD4(+) T cell peptide epitopes, which are conserved among Salmonella serovars. Immunization of Salmonella-infected mice with these peptide epitopes reduces the burden of Salmonella disease. Furthermore, we show that distinct polyfunctional (interferon-γ(+), tumor necrosis factor(+), and interleukin-2(+)) Salmonella-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 Salmonella disease. Collectively, these data could contribute to improved diagnosis of Salmonella-related diseases and rational design of Salmonella vaccines.