Cell Contact–Dependent Immunosuppression by Cd4+Cd25+Regulatory T Cells Is Mediated by Cell Surface–Bound Transforming Growth Factor β

By Kazuhiko Nakamura, A. Kitani, W. Strober. Journal of Experimental Medicine, 2001

1,860 citations recorded by the source corpus.

CD4+CD25+ T cells have been identified as a population of immunoregulatory T cells, which mediate suppression of CD4+CD25− T cells by cell–cell contact and not secretion of suppressor cytokines. In this study, we demonstrated that CD4+CD25+ T cells do produce high levels of transforming growth factor (TGF)-β1 and interleukin (IL)-10 compared with CD4+CD25− T cells when stimulated by plate-bound anti-CD3 and soluble anti-CD28 and/or IL-2, and secretion of TGF-β1 (but not other cytokines), is further enhanced by costimulation via cytotoxic T lymphocyte–associated antigen (CTLA)-4. As in prior studies, we found that CD4+CD25+ T cells suppress proliferation of CD4+CD25− T cells; however, we observed here that such suppression is abolished by the presence of anti–TGF-β. In addition, we found that CD4+CD25+ T cells suppress B cell immunoglobulin production and that anti–TGF-β again abolishes such suppression. Finally, we found that stimulated CD4+CD25+ T cells but not CD4+CD25− T cells express high and persistent levels of TGF-β1 on the cell surface. This, plus the fact that we could find no evidence that a soluble factor mediates suppression, strongly suggests that CD4+CD25+ T cells exert immunosuppression by a cell–cell interaction involving cell surface TGF-β1.

Subfields: Immunology

View Paper: https://www.semanticscholar.org/paper/6074c069cb706c3d6f1cdfd170970c7ae1d7995e

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In Immunology

1. E. Shevach
2. Shimon Sakaguchi
3. A. O’Garra
4. H. von Boehmer
5. C. Piccirillo
6. W. Strober
7. P. Vieira
8. K. Wing

Citations in the corpus

• Regulatory T Cells Selectively Express Toll-like Receptors and Are Activated by Lipopolysaccharide (2003, positive): “A previous report also described the induction of B7 expression on CD4 CD25 cells upon TCR triggering (20), a finding that we now extend to LPS activation.”
• Increase of regulatory T cells in the peripheral blood of cancer patients. (2003, background): “Moreover, in contrast to CD4 CD25 T cells, propagated CD4 CD25 T cells expressed cell surface TGF- and CTLA-4, which is in line with recent reports demonstrating the expression of these two molecules on Tregs (8, 19).”
• Infectious Tolerance (2002, background): “We and others could not detect any influence of TGFon the cell contact–mediated inhibitory function of CD25 Treg cells in vitro (2, 6), whereas several groups demonstrated that neutralizing antibodies against TGFabrogated the suppressive function of murine CD25 Treg cells in vivo (9, 15).”
• Foxp3 Expressing CD4+CD25high Regulatory T Cells Are Overrepresented in Human Metastatic Melanoma Lymph Nodes and Inhibit the Function of Infiltrating T Cells1 (2004, background): “Because real-time PCR analysis did not allow us to detect any expression of either TGF- 2 or TGF- 3 isoforms by CD4 CD25 T cells (data not shown), this suggests that the anti-TGF- 1–3 blocking Ab may exert its effect through cell surface-bound TGF- 1, which was recently implicated in the mediation o”
• Natural and Induced CD4+CD25+ Cells Educate CD4+CD25− Cells to Develop Suppressive Activity: The Role of IL-2, TGF-β, and IL-101 (2004, background): “Although some workers have reported that suppression is independent of TGFand IL-10, others have claimed that suppression can be reversed by anti-cytokine-neutralizing Abs, especially at high concentrations (23).”