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

Abstract

Summary 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.

Cytomegalovirus (CMV) Epitope–Specific CD4+ T Cells Are Inflated in HIV+ CMV+ Subjects

“…Few studies have described the TCR repertoire of HLA class II-restricted epitope-specific CD4 responses based on tetramer sorted cells, and most were conducted in vitro or without TCR sequencing (55, 73–83). Notably, some of the repertoires of these single epitope-specific T cells are diverse with over six unique, dominant TCR gene families (55, 73, 80, 83).…”

“…Notably, some of the repertoires of these single epitope-specific T cells are diverse with over six unique, dominant TCR gene families (55, 73, 80, 83). Therefore, to our knowledge, our work represents the first combination of ex vivo , class II tetramer-derived and deep sequencing-based identification of a nearly monoclonal TCR repertoire of inflated HLA-restricted epitope-specific CD4 + T cells at the resolution of the CDR3.…”

L-Asparaginase II Produced by Salmonella Typhimurium Inhibits T Cell Responses and Mediates Virulence

“…T cells play a critical role in clearance of S . Typhimurium (Dougan et al, 2011), but the T cell response to these microorganisms is thwarted during infection (Bueno et al, 2007; Ertelt et al, 2011; Johanns et al, 2010; Sad et al, 2008; Srinivasan and McSorley, 2007). …”

CD11b+Ly6ChiLy6G−Immature Myeloid Cells Recruited in Response to Salmonella enterica Serovar Typhimurium Infection Exhibit Protective and Immunosuppressive Properties

“…Immunity that eventually develops against S. Typhimurium requires humoral and cell-mediated immune responses (3). T cells, particularly gamma interferon (IFN-␥)-producing CD4 ϩ T cells, play a critical role in the clearance of S. Typhimurium (3), but T cell responses to S. Typhimurium are thwarted during infection by mechanisms that, despite recent progress (7)(8)(9)(10)(11)(12), are not well understood.…”