TY - JOUR
T1 - Tumor-derived TGF-β inhibits mitochondrial respiration to suppress IFN-γ production by human CD4+ T cells
AU - Dimeloe, Sarah
AU - Gubser, P
AU - Loeliger, J
AU - Frick, C
AU - Develioglu, Leyla
AU - Fischer, M
AU - Marquardsen, F
AU - Bantug, Glenn R
AU - Thommen, Daniela S
AU - Lecoultre, Y
AU - Zippelius, Alfred
AU - Langenkamp, A
AU - Hess, Christoph
PY - 2019/9/17
Y1 - 2019/9/17
N2 - Transforming growth factor–β (TGF-β) is produced by tumors, and increased amounts of this cytokine in the tumor microenvironment and serum are associated with poor patient survival. TGF-β–mediated suppression of antitumor T cell responses contributes to tumor growth and survival. However, TGF-β also has tumor-suppressive activity; thus, dissecting cell type–specific molecular effects may inform therapeutic strategies targeting this cytokine. Here, using human peripheral and tumor-associated lymphocytes, we investigated how tumor-derived TGF-β suppresses a key antitumor function of CD4+ T cells, interferon-γ (IFN-γ) production. Suppression required the expression and phosphorylation of Smad proteins in the TGF-β signaling pathway, but not their nuclear translocation, and depended on oxygen availability, suggesting a metabolic basis for these effects. Smad proteins were detected in the mitochondria of CD4+ T cells, where they were phosphorylated upon treatment with TGF-β. Phosphorylated Smad proteins were also detected in the mitochondria of isolated tumor-associated lymphocytes. TGF-β substantially impaired the ATP-coupled respiration of CD4+ T cells and specifically inhibited mitochondrial complex V (ATP synthase) activity. Last, inhibition of ATP synthase alone was sufficient to impair IFN-γ production by CD4+ T cells. These results, which have implications for human antitumor immunity, suggest that TGF-β targets T cell metabolism directly, thus diminishing T cell function through metabolic paralysis.
AB - Transforming growth factor–β (TGF-β) is produced by tumors, and increased amounts of this cytokine in the tumor microenvironment and serum are associated with poor patient survival. TGF-β–mediated suppression of antitumor T cell responses contributes to tumor growth and survival. However, TGF-β also has tumor-suppressive activity; thus, dissecting cell type–specific molecular effects may inform therapeutic strategies targeting this cytokine. Here, using human peripheral and tumor-associated lymphocytes, we investigated how tumor-derived TGF-β suppresses a key antitumor function of CD4+ T cells, interferon-γ (IFN-γ) production. Suppression required the expression and phosphorylation of Smad proteins in the TGF-β signaling pathway, but not their nuclear translocation, and depended on oxygen availability, suggesting a metabolic basis for these effects. Smad proteins were detected in the mitochondria of CD4+ T cells, where they were phosphorylated upon treatment with TGF-β. Phosphorylated Smad proteins were also detected in the mitochondria of isolated tumor-associated lymphocytes. TGF-β substantially impaired the ATP-coupled respiration of CD4+ T cells and specifically inhibited mitochondrial complex V (ATP synthase) activity. Last, inhibition of ATP synthase alone was sufficient to impair IFN-γ production by CD4+ T cells. These results, which have implications for human antitumor immunity, suggest that TGF-β targets T cell metabolism directly, thus diminishing T cell function through metabolic paralysis.
UR - http://www.scopus.com/inward/record.url?scp=85072296209&partnerID=8YFLogxK
U2 - 10.1126/scisignal.aav3334
DO - 10.1126/scisignal.aav3334
M3 - Article
C2 - 31530731
SN - 1945-0877
VL - 12
JO - Science signaling
JF - Science signaling
IS - 599
M1 - eaav3334
ER -