Integrated T-cell receptor and costimulatory signals determine TGF-β-dependent differentiation and maintenance of Foxp3+ regulatory T cells.

Abstract:

:Foxp3-expressing Tregs play a non-redundant role in protecting against immune pathologies. Foxp3(+) Tregs can arise intra- and extra-thymically, however, the signals directing their differentiation and maintenance in the periphery are not well understood. We show that stimulation of mouse naïve CD4(+) T cells in vitro with optimal doses of anti-CD3/anti-CD28 resulted in high frequencies of Foxp3(+) T cells via a TGF-β-dependent mechanism. Addition of TGF-β and retinoic acid overcame the inhibition of Foxp3 expression observed during high-strength anti-CD3/anti-CD28 stimulation. Reducing the strength of TCR or costimulatory signals with inhibitors of mammalian target of rapamycin (mTOR) or MEK/ERK signalling also enhanced expression of Foxp3 in a TGF-β-dependent manner. Addition of TGF-β was further required to maintain Foxp3 expression in ex vivo derived Foxp3(+) Tregs upon prolonged anti-CD3/anti-CD28 signalling. Thus, induction/maintenance of Foxp3 expression by TGF-β is modulated by the integrated strength of TCR/costimulatory signals.

journal_name

Eur J Immunol

authors

Gabryšová L,Christensen JR,Wu X,Kissenpfennig A,Malissen B,O'Garra A

doi

10.1002/eji.201041073

subject

Has Abstract

pub_date

2011-05-01 00:00:00

pages

1242-8

issue

5

eissn

0014-2980

issn

1521-4141

journal_volume

41

pub_type

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