Temporal Expression of Bacterial Proteins Instructs Host CD4 T Cell Expansion and Th17 Development

Abstract

Pathogens can substantially alter gene expression within an infected host depending on metabolic or virulence requirements in different tissues, however, the effect of these alterations on host immunity are unclear. Here we visualized multiple CD4 T cell responses to temporally expressed proteins in Salmonella-infected mice. Flagellin-specific CD4 T cells expanded and contracted early, differentiated into Th1 and Th17 lineages, and were enriched in mucosal tissues after oral infection. In contrast, CD4 T cells responding to Salmonella Type-III Secretion System (TTSS) effectors steadily accumulated until bacterial clearance was achieved, primarily differentiated into Th1 cells, and were predominantly detected in systemic tissues. Thus, pathogen regulation of antigen expression plays a major role in orchestrating the expansion, differentiation, and location of antigen-specific CD4 T cells in vivo.

Author Summary

Pathogens alter protein expression in an infected host, depending on metabolic or virulence requirements, but the effect of these changes on the immune response is unclear. We identified new class-II epitopes within Salmonella type-III secretion system effector proteins and generated a methodology to visualize endogenous T cells responding to these epitopes. Our study shows that Salmonella flagellin generates a mixed Th1 and Th17 response that contracts early and is enriched in mucosal tissues. In contrast, we found that Salmonella T3SS effectors generate a sustained Th1 response that requires a persisting infection and is enriched in systemic tissues. These data demonstrate that in vivo antigen regulation substantially alters the antigen specificity, helper differentiation, and anatomical location of pathogen-specific CD4 T cells.