Resistance to TGFβ suppression and improved anti-tumor responses in CD8+ T cells lacking PTPN22

Transforming growth factor beta (TGF beta) is important in maintaining self-tolerance and inhibits T cell reactivity. We show that CD8(+) T cells that lack the tyrosine phosphatase Ptpn22, a major predisposing gene for autoimmune disease, are resistant to the suppressive effects of TGF beta. Resistance to TGF beta suppression, while disadvantageous in autoimmunity, helps Ptpn22(-/)-T cells to be intrinsically superior at clearing established tumors that secrete TGF beta. Mechanistically, loss of Ptpn22 increases the capacity of T cells to produce IL-2, which overcomes TGF beta-mediated suppression. These data suggest that a viable strategy to improve anti-tumor adoptive cell therapy may be to engineer tumor-restricted T cells with mutations identified as risk factors for autoimmunity.