Antigen-specific peripheral shaping of the natural regulatory T cell population

• Published in: The Journal of experimental medicine 2008-12, Vol.205 (13), p.3105-3117
• Main Authors: Lathrop, Stephanie K, Santacruz, Nicole A, Pham, Dominic, Luo, Jingqin, Hsieh, Chyi-Song
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Animals; Antigens - immunology; CD4-Positive T-Lymphocytes - immunology; Forkhead Transcription Factors - genetics; Forkhead Transcription Factors - immunology; Gene Expression Profiling; Hyaluronan Receptors - genetics; Hyaluronan Receptors - immunology; Mice; Mice, Transgenic; Molecular Sequence Data; Receptors, Antigen, T-Cell - genetics; Receptors, Antigen, T-Cell - immunology; Sequence Alignment; T-Lymphocyte Subsets - immunology; T-Lymphocytes, Regulatory - immunology
• ISSN: 0022-1007; 1540-9538
• DOI: 10.1084/jem.20081359

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 TCRbeta 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(hi)Foxp3(-)) but not naive (CD44(lo)Foxp3(-)) 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.