The Journal of Experimental Medicine
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Published online 8 November 2004 doi:10.1084/jem.20041022
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 200, Number 10, 1221-1230
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Number of T Reg Cells That Differentiate Does Not Increase upon Encounter of Agonist Ligand on Thymic Epithelial Cells

Hisse-Martien van Santen1,2, Christophe Benoist1,2, and Diane Mathis1,2

1 Section on Immunology and Immunogenetics, Joslin Diabetes Center
2 Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02215

Address correspondence to Diane Mathis and Christophe Benoist, Section of Immunology and Immunogenetics, Joslin Diabetes Center, Dept. of Medicine, Brigham and Women's Hospital, Harvard Medical School, One Joslin Place, Boston, MA 02215. Phone: (617) 264-2745; Fax: (617) 264-2744; email: cbdm{at}joslin.harvard.edu

It has been reported that the differentiation of CD4+CD25+ regulatory T cells (T reg cells) can be induced by agonist peptide/major histocompatibility complex ligands in the thymus. Exploiting a transgenic mouse line wherein expression of a particular T cell epitope can be controlled temporally and quantitatively, we found that diversion of differentiating thymocytes into the FoxP3 T reg cell pathway by this agonist ligand was essentially nonexistent. However, CD4+CD25+ thymocytes were much less sensitive than their CD4+CD25– companions, by two to three orders of magnitude, to agonist-induced clonal deletion, such that their proportion increased, giving the false impression of induced differentiation. To account for these and prior observations, one can propose that differentiation along the CD4+CD25+ pathway is induced by cues other than recognition of self-agonist cues, which are poorly read by thymocytes, whose T cell receptors are conducive to selection toward the conventional CD4+CD25– lineage. Thus, selective survival, rather than induced differentiation, may explain the apparent enrichment observed here and in previous studies.

Key Words: Foxp3 • thymocytes • clonal deletion • inducible expression • transgenic

Abbreviations used in this paper: CLIP, class II–associated invariant chain peptide; MCC, moth cytochrome c.; T reg cell, regulatory T cell; tet, tetracycline; TIM, tet-regulatable invariant chain with MCC.


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