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The Journal of Immunology, 2004, 173: 236-244.
Copyright © 2004 by The American Association of Immunologists

CD4+ CD25+ Regulatory T Cell Repertoire Formation in Response to Varying Expression of a neo-Self-Antigen 1

Melissa A. Lerman, Joseph Larkin, III, Cristina Cozzo, Martha S. Jordan2 and Andrew J. Caton3

Wistar Institute, Philadelphia, PA 19104

We have examined the development of self-peptide-specific CD4+CD25+ regulatory T cells in lineages of transgenic mice that express the influenza virus PR8 hemagglutinin (HA) under the control of several different promoters (HA transgenic mice). By mating these lineages with TS1-transgenic mice expressing a TCR that recognizes the major I-Ed-restricted determinant from HA (site 1 (S1)), we show that S1-specific T cells undergo selection to become CD4+CD25+ regulatory T cells in each of the lineages, although in varying numbers. In some lineages, S1-specific CD4+CD25+ regulatory T cells are highly abundant; indeed, TS1xHA-transgenic mice can contain as many S1-specific CD4+ T cells as are present in TS1 mice, which do not express the neo-self HA. In another lineage, however, S1-specific thymocytes are subjected to more extensive deletion and far fewer S1-specific CD4+CD25+ regulatory T cells accumulate in the periphery. We show that radioresistant stromal cells can direct both deletion and CD4+CD25+ regulatory T cell selection of S1-specific thymocytes. Interestingly, even though their numbers can vary, the S1-specific CD4+CD25+ regulatory T cells in all cases coexist with clonally related CD4+CD25– T cells that lack regulatory function. These findings show that the formation of the CD4+CD25+ regulatory T cell repertoire is sensitive to variations in the expression of self-peptides.




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