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

• Published in: Nature communications Vol. 8; no. 1; pp. 1343 - 10
• Main Authors: Brownlie, Rebecca J., Garcia, Celine, Ravasz, Mate, Zehn, Dietmar, Salmond, Robert J., Zamoyska, Rose
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 07.11.2017; Nature Publishing Group; Nature Portfolio
• Subjects: 631/250/251/1567; 631/67/1059/2325; 631/67/327; CD8 antigen; Clearing; Humanities and Social Sciences; Immunological tolerance; Interleukin 2; Lymphocytes; Lymphocytes T; multidisciplinary; Mutation; Protein-tyrosine-phosphatase; Risk analysis; Risk factors; Science; Science (multidisciplinary); Transforming growth factor; Transforming growth factor-b; Tumors; Tyrosine
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-017-01427-1

Transforming growth factor β (TGFβ) 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 TGFβ. Resistance to TGFβ suppression, while disadvantageous in autoimmunity, helps Ptpn22 −/− T cells to be intrinsically superior at clearing established tumors that secrete TGFβ. Mechanistically, loss of Ptpn22 increases the capacity of T cells to produce IL-2, which overcomes TGFβ-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. TGFβ secretion in the tumor microenvironment inhibits T cell-mediated anti-tumor immune responses. Here the authors show that a mutation predisposing to autoimmune diseases confers T cells resistance to TGFβ inhibitory action and could be exploited to engineer immunotherapies for TGFβ secreting tumors.