Antigen exposure shapes the ratio between antigen-specific Tregs and conventional T cells in human peripheral blood

Abstract

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 selfreactive 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.regulatory T cells | antigen specificity | repertoire | human | influenza

Identification of Natural Regulatory T Cell Epitopes Reveals Convergence on a Dominant Autoantigen

“…Previous reports demonstrate that a minor fraction of Foxp3 + Treg cells can be identified within antigen-specific T cell populations reactive to both self and foreign pMHC-II (Malhotra et al, 2016; Moon et al, 2011; Su et al, 2016). However, these populations do not reflect naturally occurring antigen specificities that drive the robust selection of Treg cells in the thymus.…”

The multiple pathways to autoimmunity

“…Interestingly, T reg cells generated in the perinatal period persist and effectively inhibit autoimmunity throughout life 51 . The overall frequency of the polyclonal T reg cell population is approximately 5–15% of CD4 + T cells, but the ratio between antigen-specific T reg and effector T cells decreases during an ongoing immune response, presumably to improve anti-pathogen immunity 52 . T reg cells may also promote tissue repair in response to inflammatory factors released from damaged cells 53 and exert a regenerative effect in the CNS 54 and skeletal muscle 55 .…”

Opposing peripheral fates of tissue‐restricted self antigen‐specific conventional and regulatory CD4+ T cells

“…Using tetramers to directly identify and characterize endogenous self antigen-specific T cells, we and others have revealed that the impact of deletion on peripheral frequencies of self antigen-specific T cells is much less complete than previously anticipated [8][9][10][11]. Moreover, Foxp3 + Tregs comprise only a minor fraction of these cells, leaving open the question of how Foxp3 − conventional cells remain tolerant in the steady state [8][9][10]12].…”