The Foxp3-expressing subset of regulatory CD4+ T cells have defined Ag specificity and play essential roles in maintaining peripheral tolerance by suppressing the activation of self-reactive T cells. Similarly, during chronic infection, pathogen-specific Foxp3-expressing CD4+ T cells expand and actively suppress pathogen-specific effector T cells. Herein, we used MHC class II tetramers and Foxp3gfp knockin mice to track the kinetics and magnitude whereby pathogen-specific Foxp3+CD4+ and Foxp3−CD4+ cells are primed and expand after acute infection with recombinant Listeria monocytogenes (Lm) expressing the non-“self”-Ag 2W1S52–68. We demonstrate that Lm infection selectively primes proliferation, expansion, and subsequent contraction of Lm-specific Foxp3− effector CD4+ cells, while the numbers of Lm-specific Foxp3+CD4+ regulatory cells remain essentially unchanged. In sharp contrast, purified 2W1S52–68 peptide primes coordinated expansion of both Foxp3+ regulatory and Foxp3− effector T cells with the same Ag specificity. Taken together, these results indicate selective priming and expansion of Foxp3− CD4 T cells is a distinguishing feature for acute bacterial infection.

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T cell activation required for host defense against infection is an intricately regulated and precisely controlled process. Although in vitro studies indicate that three distinct stimulatory signals are required for T cell activation, the precise contribution of each signal in regulating T cell proliferation and differentiation after in vivo infection is unknown. In this study, altered peptide ligands (APLs) derived from the protective Salmonella-specific FliC Ag and CD4+ T cells specific for the immune-dominant FliC431–439 peptide within this Ag were used to determine how changes in TCR stimulation impact CD4+ T cell proliferation, differentiation, and protective potency. To explore the prevalence and potential use of altered TCR stimulation by bacterial pathogens, naturally occurring APLs containing single amino acid substitutions in putative TCR contact residues within the FliC431–439 peptide were identified and used for stimulation under both noninfection and infection conditions. On the basis of this analysis, naturally-occurring APLs that prime proliferation of FliC-specific CD4+ T cells either more potently or less potently compared with the wild-type FliC431–439 peptide were identified. Remarkably, despite these differences in proliferation, all of the APLs primed reduced IFN-γ production by FliC431–439-specific CD4+ T cells after stimulation in vivo. Moreover, after expression of the parental FliC431–439 peptide or each APL in recombinant Listeria monocytogenes, only CD4+ T cells stimulated with the wild-type FliC431–439 peptide conferred significant protection against challenge with virulent Salmonella. These results reveal important and unanticipated roles for TCR stimulation in controlling pathogen-specific CD4+ T cell proliferation, differentiation, and protective potency.

The pathogenesis of persistent infection is dictated by the balance between opposing immune activation and suppression signals. Although regulatory T cells (Tregs) have been widely implicated to control host defense against infection, their role in dictating the natural progression of persistent infection remains incompletely defined. Herein, a sharp dichotomy in infection tempo between early and late time points during persistent Salmonella infection is demonstrated. Early after infection, blunted effector T cell activation and increasing bacterial burden coincide with enhanced Treg suppressive potency. Reciprocally, at later time points, robust effector T cell activation and bacterial clearance occur in parallel with diminished Treg suppression. By enumerating the relative impact of Treg ablation on infection outcome at both early and late time points of persistent infection, the role of Treg suppressive potency in dictating the natural progression of infection was verified. Thus, dynamic control of Treg suppressive potency dictates the tempo of persistent bacterial infection.