CD4+CD25+ regulatory T cells inhibit natural killer cell functions in a transforming growth factor–β–dependent manner

By François Ghiringhelli, C. Ménard, M. Terme, C. Flament, J. Taieb, N. Chaput, P. Puig, S. Novault, B. Escudier, É. Vivier and 12 more. Journal of Experimental Medicine, 2005

877 citations recorded by the source corpus.

Tumor growth promotes the expansion of CD4+CD25+ regulatory T (T reg) cells that counteract T cell–mediated immune responses. An inverse correlation between natural killer (NK) cell activation and T reg cell expansion in tumor-bearing patients, shown here, prompted us to address the role of T reg cells in controlling innate antitumor immunity. Our experiments indicate that human T reg cells expressed membrane-bound transforming growth factor (TGF)–β, which directly inhibited NK cell effector functions and down-regulated NKG2D receptors on the NK cell surface. Adoptive transfer of wild-type T reg cells but not TGF-β −/− T reg cells into nude mice suppressed NK cell–mediated cytotoxicity, reduced NKG2D receptor expression, and accelerated the growth of tumors that are normally controlled by NK cells. Conversely, the depletion of mouse T reg cells exacerbated NK cell proliferation and cytotoxicity in vivo. Human NK cell–mediated tumor recognition could also be restored by depletion of T reg cells from tumor-infiltrating lymphocytes. These findings support a role for T reg cells in blunting the NK cell arm of the innate immune system.

Subfields: Immunology

View Paper: https://www.semanticscholar.org/paper/2b4a6fa92b925ec42124486775e0c8031b98535d

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In Immunology

1. L. Zitvogel
2. É. Vivier
3. R. Vance
4. S. Ugolini
5. D. Raulet
6. P. Puig
7. F. Martin
8. François Ghiringhelli

Citations in the corpus

• 5-Fluorouracil selectively kills tumor-associated myeloid-derived suppressor cells resulting in enhanced T cell-dependent antitumor immunity. (2010, background): “Cyclophosphamide had a T-dependent antitumor effect that was annihilated by an adoptive transfer of Treg cells (25, 30).”
• Cancer-Expanded Myeloid-Derived Suppressor Cells Induce Anergy of NK Cells through Membrane-Bound TGF-β11 (2009, background): “For example, tumor growth promotes the expansion of Tregs and Tregs could suppress NK cell functions including cytotoxicity, NKG2D expression, and IFN- production in human and mice (21, 22).”
• Metronomic cyclophosphamide regimen selectively depletes CD4+CD25+ regulatory T cells and restores T and NK effector functions in end stage cancer patients (2007, background): “NK and T cells inhibition by Treg is associated with a poor prognosis outcome of malignancy in human [8, 9].”
• Granzyme B and perforin are important for regulatory T cell-mediated suppression of tumor clearance. (2007, background): “Recent reports from two other groups have also shown that Treg cells can suppress NK cell-mediated im- mune responses (Ghiringhelli et al., 2005; Barao et al., 2006).”
• Self-tolerance of natural killer cells (2006, result): “Two intriguing recent reports have provided evidence that T Reg cells can inhibit the function of NK cell”
• Functions of natural killer cells (2008, background): “, and by regulatory T cells through a TGF-β-dependent mechanism in human and mic”