TGF-β inhibits the activation and functions of NK cells by repressing the mTOR pathway

Abstract

Transforming growth factor-β (TGF-β) is a major immunosuppressive cytokine that maintains immune homeostasis and prevents autoimmunity through its antiproliferative and anti-inflammatory properties in various immune cell types. We provide genetic, pharmacologic, and biochemical evidence that a critical target of TGF-β signaling in mouse and human natural killer (NK) cells is the serine and threonine kinase mTOR (mammalian target of rapamycin). Treatment of mouse or human NK cells with TGF-β in vitro blocked interleukin-15 (IL-15)-induced activation of mTOR. TGF-β and the mTOR inhibitor rapamycin both reduced the metabolic activity and proliferation of NK cells and reduced the abundances of various NK cell receptors and the cytotoxic activity of NK cells. In vivo, constitutive TGF-β signaling or depletion of mTOR arrested NK cell development, whereas deletion of the TGF-β receptor subunit TGF-βRII enhanced mTOR activity and the cytotoxic activity of the NK cells in response to IL-15. Suppression of TGF-β signaling in NK cells did not affect either NK cell development or homeostasis; however, it enhanced the ability of NK cells to limit metastases in two different tumor models in mice. Together, these results suggest that the kinase mTOR is a crucial signaling integrator of pro- and anti-inflammatory cytokines in NK cells. Moreover, we propose that boosting the metabolic activity of antitumor lymphocytes could be an effective strategy to promote immune-mediated tumor suppression.

Epithelial-mesenchymal transition leads to NK cell–mediated metastasis-specific immunosurveillance in lung cancer

“…Moreover, we did not observe any effect of NK cell depletion on the growth of the primary tumors. TGF-β is known to inhibit NK cell function (48,49), and the TGF-β-rich tumor microenvironment may explain why NK cell depletion has no effect on the primary tumor growth. However, TGF-β levels in circulation or at the site of metastasis are substantially lower than those in the primary tumor microenvironment, enabling metastasis-specific immunosurveillance.…”

What Fuels Natural Killers? Metabolism and NK Cell Responses

“…Upon immune activation, lymphocytes, including NK cells, increase glucose metabolism through glycolysis metabolizing much of the glucose into lactate, which is secreted from the cell, a process called “aerobic glycolysis” (14–17). Aerobic glycolysis is adopted by cells engaging in robust growth and proliferation because it provides the biosynthetic precursors that are essential for the synthesis of nucleotides, amino acids, and lipids (Figure 1) (18, 19).…”

Tissue-Specific Control of Tissue-Resident Memory T Cells

“…90 Interestingly, low dose rapamycin treatment during the effector phase of an immune response inhibits the expression of gut homing receptors and greatly reduces the formation of gut T RM population. 91 Considering that TGF-β inhibits the serine and threonine kinase mammalian target of rapamycin (mTOR) in NK cells, 92 the possible crosstalk between TGF-β signaling and mTOR pathway in gut T RM cell biology warrants future investigation.…”