TGF-β requires CTLA-4 early after T cell activation to induce foxP3 and generate adaptive CD4+CD25+ regulatory cells

Song Guo Zheng, Ju Hua Wang, William Stohl, Kyoung Soo Kim, J. Dixon Gray, David A. Horwitz

Research output: Contribution to journalArticlepeer-review

241 Scopus citations


Although positive CD28 costimulation is needed for the generation of natural CD4+CD25+ regulatory T cells, we report that negative CTLA-4 costimulation is necessary for generating phenotypically and functionally similar adaptive CD4+CD25+ suppressor cells. TGF-β could not induce CD4+CD25- cells from CTLA-4-/- mice to express normal levels of FoxP3 or to develop suppressor activity. Moreover, blockade of CTLA-4 following activation of wild-type CD4+ cells abolished the ability of TGF-β to induce FoxP3-expressing mouse suppressor cells. TGF-β accelerated expression of CTLA-4, and time course studies suggested that CTLA-4 ligation of CD80 shortly after T cell activation enables TGF-β to induce CD4+CD25 - cells to express FoxP3 and develop suppressor activity. TGF-β also enhanced CD4+ cell expression of CD80. Thus, CTLA-4 has an essential role in the generation of acquired CD4+CD25+ suppressor cells in addition to its other inhibitory effects. Although natural CD4+CD25+ cells develop normally in CTLA-4-/- mice, the lack of TGF-β-induced, peripheral CD4+CD25+ suppressor cells in these mice may contribute to their rapid demise.

Original languageEnglish (US)
Pages (from-to)3321-3329
Number of pages9
JournalJournal of Immunology
Issue number6
StatePublished - Mar 15 2006

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Immunology


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