Selective culling of high avidity antigen-specific CD4 ⁺ T cells after virulent Salmonella infection

Typhoid fever is a persistent infection caused by host-adapted Salmonella strains adept at circumventing immune-mediated host defences. Given the importance of T cells in protection, the culling of activated CD4 ⁺ T cells after primary infection has been proposed as a potential immune evasion strategy used by this pathogen. We demonstrate that the purging of activated antigen-specific CD4 ⁺ T cells after virulent Salmonella infection requires SPI-2 encoded virulence determinants, and is not restricted only to cells with specificity to Salmonella-expressed antigens, but extends to CD4 ⁺ T cells primed to expand by co-infection with recombinant Listeria monocytogenes. Unexpectedly, however, the loss of activated CD4 ⁺ T cells during Salmonella infection demonstrated using a monoclonal population of adoptively transferred CD4 ⁺ T cells was not reproduced among the endogenous repertoire of antigen-specific CD4 ⁺ T cells identified with MHC class II tetramer. Analysis of T-cell receptor variable segment usage revealed the selective loss and reciprocal enrichment of defined CD4 ⁺ T-cell subsets after Salmonella co-infection that is associated with the purging of antigen-specific cells with the highest intensity of tetramer staining. Hence, virulent Salmonella triggers the selective culling of high avidity activated CD4 ⁺ T-cell subsets, which re-shapes the repertoire of antigen-specific T cells that persist later after infection.