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Published online before print February 12, 2008

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(Journal of Leukocyte Biology. 2008;83:1230-1239.)
© 2008 by Society for Leukocyte Biology

De novo induction of antigen-specific CD4+CD25+Foxp3+ regulatory T cells in vivo following systemic antigen administration accompanied by blockade of mTOR

Johnthomas Kang^*, Stephen J. Huddleston, Joanne M. Fraser^* and Alexander Khoruts^*,1

^* Center for Immunology and Department of Medicine and
Department of Surgery, University of Minnesota, Minneapolis, Minnesota, USA

¹Correspondence: University of Minnesota, Department of Medicine, 6-134 Niels Hasselmo Hall, 312 Church St. S.E., Minneapolis, MN 55455, USA. E-mail: khoru001{at}umn.edu

Although regulatory CD4+CD25+ forkhead box p3+ (Foxp3+) T cells (Tregs) are generally thought to arise in the thymus as a separate lineage of CD4 T cells, they can also be induced de novo in the periphery. Peripheral development of Tregs from naïve T cells is favored by low-intensity activation and absence of inflammation. We show here that absence of CD28 costimulation results in a modest decrease in activation of naïve, antigen-specific CD4 T cells under noninflammatory conditions and benefits their initial Foxp3 induction. However, expression of Foxp3 following T cell activation without CD28 costimulation remains sensitive to the antigen dose. Furthermore, basal CD28 costimulation is critical for survival of the induced Foxp3+ CD4 T cells, and their accumulation is abrogated in the absence of CD28. In contrast, pharmacologic blockade of mammalian target of rapamycin enhances lasting induction of Tregs, irrespective of the initial antigen dose used to activate the antigen-specific T cells. This finding may have important practical, clinical implication in development of tolerance protocols.

Key Words: tolerance/suppression/anergy • cell differentiation

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