TGF-beta: the missing link in CD4+CD25+ regulatory T cell-mediated immunosuppression

Cytokine Growth Factor Rev. 2003 Apr;14(2):85-9. doi: 10.1016/s1359-6101(03)00003-0.


A unique population of CD4(+) T lymphocytes that constitutively express CD25 has been recognized as anergic/suppressor cells. While the immunosuppressive activity of these CD4(+)CD25(+) cells has been validated and implicated in tolerance, autoimmunity, transplantation, cancer and infectious diseases, the mechanism(s) by which they function still remains controversial. Although the involvement of TGF-beta was initially discounted, emerging evidence now links this cytokine with CD4(+)CD25(+) T cell-mediated suppression of antigen-activated T cells. In this perspective, we summarize recently published studies, as well as our own data, which shed light on how cell membrane-bound TGF-beta can deliver a regulatory signal to target cells via a contact-dependent process. Moreover, suppressor T cell function is a complex process, tightly regulated by multiple factors, including IL-2, cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) and glucocorticoid induced TNF receptor (GITR). Collectively, multiple previously unconnected puzzle pieces are beginning to be linked into a more coherent, albeit incomplete picture of CD4(+)CD25(+) T cell-mediated suppression.

Publication types

  • Review

MeSH terms

  • Animals
  • CD4 Antigens / biosynthesis*
  • Humans
  • Immune Tolerance
  • Immunosuppression*
  • Models, Biological
  • Receptors, Interleukin-2 / biosynthesis*
  • Signal Transduction
  • T-Lymphocytes / metabolism*
  • Transforming Growth Factor beta / metabolism
  • Transforming Growth Factor beta / physiology*


  • CD4 Antigens
  • Receptors, Interleukin-2
  • Transforming Growth Factor beta