Antigen exposure shapes the ratio between antigen-specific Tregs and conventional T cells in human peripheral blood.
The T-cell receptor (TCR) is required for maturation and function of regulatory T cells (Tregs), but the ligand specificities of Tregs outside the context of transgenic TCRs are largely unknown. Using peptide-MHC tetramers, we isolated rare specific Foxp3+cells directly ex vivo from adult peripheral blood and defined their frequency and phenotype. We find that a proportion of circulating Tregs recognize foreign antigens and the frequency of these cells are similar to that of self-reactive Tregs in the absence of cognate infection. In contrast, the frequencies of Tregs that recognize some common microbial antigens are significantly reduced in the blood of most adults. Exposure to peripheral antigens likely has a major influence on the balance between Tregs and conventional T-cell subsets because a larger proportion of flu-specific T cells has a regulatory cell phenotype in the cord blood. Consistent with this finding, we show that lymphocytic choriomeningitis virus infection can directly modulate the ratio of virus-specific effectors and Tregs in mice. The resulting change in the balance within an antigen-specific T-cell population further correlates with the magnitude of effector response and the chronicity of infection. Taken together, our data highlight the importance of antigen specificity in the functional dynamics of the T-cell repertoire. Each specific population of CD4+T cells in human peripheral blood contains a subset of Tregs at birth, but the balance between regulatory and effector subsets changes in response to peripheral antigen exposure and this could impact the robustness of antipathogen immunity.
Department of Medicine, Division of Rheumatology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104; Department of Medicine, Division of Immunology and Rheumatology, Stanford University School of Medicine, Stanford, CA 94304; laurasu@upenn.edu mmdavis@stanford.edu.
Laura F
LF
Su
Department of Medicine, Division of Rheumatology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104.
Daniel
D
Del Alcazar
Department of Microbiology and Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104.
Erietta
E
Stelekati
Department of Microbiology and Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104.
E John
EJ
Wherry
Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA 94304; Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA 94304 laurasu@upenn.edu mmdavis@stanford.edu.
Mark M
MM
Davis
D000818:Animals; D000941:Antigens / Q000276:immunology*; D000956:Antigens, Viral / Q000276:immunology; D015415:Biomarkers; D016207:Cytokines / Q000378:metabolism; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D005312:Fetal Blood; D020869:Gene Expression Profiling; D015804:HLA-DR4 Antigen / Q000235:genetics / Q000276:immunology; D054884:Host-Pathogen Interactions / Q000276:immunology; D006801:Humans; D007156:Immunologic Memory; D008213:Lymphocyte Activation / Q000276:immunology*; D018655:Lymphocyte Count; D051379:Mice; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism; D059467:Transcriptome
D000941:Antigens; D000956:Antigens, Viral; D015415:Biomarkers; D016207:Cytokines; D018984:Epitopes, T-Lymphocyte; D015804:HLA-DR4 Antigen
antigen specificity; human; influenza; regulatory T cells; repertoire
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