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

TLDR

Tumor growth drives expansion of CD4⁺CD25⁺ regulatory T cells that dampen T‑cell–mediated immune responses. The study investigates whether these regulatory T cells suppress innate antitumor immunity by inhibiting natural killer (NK) cell activation. Human CD4⁺CD25⁺ regulatory T cells express membrane‑bound TGF‑β, which directly suppresses NK effector functions and down‑regulates NKG2D receptors; adoptive transfer of wild‑type but not TGF‑β‑deficient T reg cells into mice suppresses NK cytotoxicity, reduces NKG2D expression, and accelerates tumor growth, whereas depletion of T reg cells enhances NK proliferation, cytotoxicity, and restores tumor recognition, demonstrating that T reg cells blunt the NK arm of innate immunity.

Abstract

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.