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TCR Repertoire and Foxp3 Expression Define Functionally Distinct Subsets of CD4⁺ Regulatory T Cells¹

Michal Kuczma^*, Iwona Pawlikowska, Magdalena Kopij^*, Robert Podolsky^*, Grzegorz A. Rempala and Piotr Kraj^2,*

^* Center for Biotechnology and Genomic Medicine, Department of Biostatistics and the Cancer Center, Medical College of Georgia, Augusta, GA 30912

Despite extensive research efforts to characterize peripheral regulatory T (T_reg) cells expressing transcription factor Foxp3, their subset complexity, phenotypic characteristics, TCR repertoire and Ag specificities remain ambiguous. In this study, we identify and define two subsets of peripheral T_reg cells differing in Foxp3 expression level and TCR repertoires. T_reg cells expressing a high level of Foxp3 and TCRs not used by naive CD4⁺ T cells present a stable suppressor phenotype and dominate the peripheral T_reg population in unmanipulated mice. The second T_reg subset, expressing a lower level of Foxp3 and using TCRs shared with naive CD4⁺ T cells constitutes a small fraction of all T_reg cells in unmanipulated mice and enriches T_reg population with the same Ag specificities as expressed by activated/effector T cells. This T_reg subset undergoes extensive expansion during response to Ag when it becomes a major population of Ag-specific T_reg cells. Thus, T_reg cells expressing TCRs shared with naive CD4⁺ T cells have a flexible phenotype and may down-regulate Foxp3 expression which may restore immune balance at the conclusion of immune response or convert these cells to effector T cells producing inflammatory cytokines.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by Grants R01 CA107349-01A1 (to P.K.) and 1R01DE019243-01 (to G.A.R.) from the National Institutes of Health.

² Address correspondence and reprint requests to Dr. Piotr Kraj, Center for Biotechnology and Genomic Medicine, Medical College of Georgia, CA-4141, Augusta, GA 30912. E-mail address: pkraj{at}mail.mcg.edu

³ Abbreviations used in this paper: T_reg, regulatory T; nT_reg, natural T_reg; aT_reg, adoptive T_reg; T_eff, effector T.