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Published online before print May 2, 2007

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© by The Society for Leukocyte Biology
Journal of Leukocyte Biology, doi:10.1189/jlb.1006644

Received for publication October 25, 2006.
Revised March 13, 2007.
Accepted for publication March 30, 2007.

Article

TGF-1 modulates Foxp3 expression and regulatory activity in distinct CD4⁺ T cell subsets

Department of Microbiology and Immunology and Strategic Training Centre in Infectious Diseases and Autoimmunity, McGill University, Montreal, Quebec, Canada

^@ To whom correspondence should be addressed. E-mail: Ciro.piccirillo{at}mcgill.ca.

	Abstract

Although forkhead box p3 (Foxp3) expression is restricted to naturally occurring CD4⁺ regulatory T cells (T_REG), little is known about the various signals that regulate it in T cells. As TGF- has been reported to modulate Foxp3 expression in T cells, we investigated its effects on the induction or maintenance of regulatory functions in different CD4⁺ T cell subsets. TGF-1 priming was able to promote differentiation of T_REG cells from nonregulatory CD4⁺CD25^- T cells in a concentration-dependent manner through Foxp3 induction. As CD4⁺CD25^- T cells remain a highly heterogeneous population with variable degrees of antigen experience, we then examined the effect of TGF-1 on naive CD4⁺CD25^-CD45RB^HIGH T cells. Freshly isolated or TGF-1-treated CD4⁺CD25^-CD45RB^HIGH T cells never displayed any regulatory functions or significant Foxp3 expression following TCR activation. In stark contrast, freshly isolated CD4⁺CD25^-CD45RB^LOW cells, albeit expressing low levels of Foxp3 mRNA and protein, were unable to suppress CD4⁺ effector T cell proliferation but acquired regulatory activity and de novo Foxp3 expression following TGF-1 exposure. Furthermore, suppression was IL-10-dependent, as anti-IL-10 receptor antibody treatment abrogated this suppression completely, consistent with the ability of TGF-1-treated CD4⁺CD25^-CD45RB^LOW to synthesize IL-10 mRNA upon restimulation in vitro. Last, we show that TGF-1 treatment or blockade did not lead to enhanced expansion or function of naturally occurring CD4⁺CD25⁺ T_REG cells, although it maintained Foxp3 mRNA and protein expression. Altogether, TGF-1 promotes the induction of IL-10-secreting CD4⁺ T_REG cells from CD4⁺CD25^-CD45RB^LOW precursors through de novo Foxp3 production and maintains natural T_REG cell peripheral homeostasis by sustaining Foxp3 expression.

Key Words: CD4⁺CD25⁺ regulatory T cells • IL-10 • suppression • tolerance

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