Although regulatory T (T reg) cells are thought to develop primarily in the thymus, the peripheral events that shape the protective T reg cell population are unclear. We analyzed the peripheral CD4+ T cell receptor (TCR) repertoire by cellular phenotype and location in mice with a fixed TCR ß chain. We found that T reg (Foxp3+) cells showed a marked skewing of TCR usage by anatomical location in a manner similar to antigen-experienced (CD44 hiFoxp3–) but not naive (CD44 loFoxp3–) cells, even though CD44 hi and T reg cells used mostly dissimilar TCRs. This was likely unrelated to peripheral conversion, which we estimate generates only a small percentage of peripheral T reg cells in adults. Conversion was readily observed, however, during the immune response induced by Foxp3–cells in lymphopenic hosts. Interestingly, the converted Foxp3+ and expanded Foxp3–TCR repertoires were different, suggesting that generation of Foxp3+ cells is not an automatic process upon antigen activation of Foxp3–T cells. Retroviral expression of these TCRs in primary monoclonal T cells confirmed that conversion did not require prior cellular conditioning. Thus, these data demonstrate that TCR specificity plays a crucial role in the process of peripheral conversion and in shaping the peripheral T reg cell population to the local antigenic landscape.

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