title: The differentiation and plasticity of Tc17 cells are regulated by CTLA-4-mediated effects on STATs.
abstract: As the blockade of inhibitory surface-molecules such as CTLA-4 on T cells has led to recent advances in antitumor immune therapy, there is great interest in identifying novel mechanisms of action of CD8+T cells to evoke effective cytotoxic antitumor responses. Usingin vitroandin vivomodels, we investigated the molecular pathways underlying the CTLA-4-mediated differentiation of IL-17-producing CD8+T cells (Tc17 cells) that strongly impairs cytotoxicity. Our studies demonstrate that Tc17 cells lacking CTLA-4 signaling have limited production of STAT3-target gene products such as IL-17, IL-21, IL-23R and RORγt. Upon re-stimulation with IL-12, these cells display fast downregulation of Tc17 hallmarks and acquire Tc1 characteristics such as IFNγ and TNF-α co-expression, which is known to correlate with tumor control. Indeed, upon adoptive transfer, these cells were highly efficient in the antigen-specific rejection of established OVA-expressing B16 melanomain vivo. Mechanistically, in primary and re-stimulated Tc17 cells, STAT3 binding to the IL-17 promoter was strongly augmented by CTLA-4, associated with less binding of STAT5 and reduced relative activation of STAT1 which is known to block STAT3 activity. Inhibiting CTLA-4-induced STAT3 activity reverses enhancement of signature Tc17 gene products, rendering Tc17 cells susceptible to conversion to Tc1-like cells with enhanced cytotoxic potential. Thus, CTLA-4 critically shapes the characteristics of Tc17 cells by regulating relative STAT3 activation, which provides new perspectives to enhance cytotoxicity of antitumor responses.
authors.affiliation: Department of Pediatrics, University Hospital, Health Campus Immunology, Infectiology and Inflammation, Otto-von-Guericke-University , Magdeburg, Germany.
authors.forename: Aditya
authors.initials: A
authors.lastname: Arra
authors.affiliation: Department of Pediatrics, University Hospital, Health Campus Immunology, Infectiology and Inflammation, Otto-von-Guericke-University , Magdeburg, Germany.
authors.forename: Holger
authors.initials: H
authors.lastname: Lingel
authors.affiliation: Institut für Chemie und Biochemie, Protein Biochemistry Group, Freie Universität, Berlin, Germany; Mass Spectrometry Group, Leibniz-Institut für Molekulare Pharmakologie, Berlin, Germany.
authors.forename: Benno
authors.initials: B
authors.lastname: Kuropka
authors.affiliation: Department of Pediatrics, University Hospital, Health Campus Immunology, Infectiology and Inflammation, Otto-von-Guericke-University , Magdeburg, Germany.
authors.forename: Jonas
authors.initials: J
authors.lastname: Pick
authors.affiliation: Department of Hematology and Oncology, University Hospital, Health Campus Immunology, Infectiology and Inflammation, Otto-von-Guericke-University , Magdeburg, Germany.
authors.forename: Tina
authors.initials: T
authors.lastname: Schnoeder
authors.affiliation: Department of Hematology and Oncology, University Hospital, Health Campus Immunology, Infectiology and Inflammation, Otto-von-Guericke-University , Magdeburg, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Fischer
authors.affiliation: Institut für Chemie und Biochemie, Protein Biochemistry Group, Freie Universität, Berlin, Germany; Mass Spectrometry Group, Leibniz-Institut für Molekulare Pharmakologie, Berlin, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Freund
authors.affiliation: Department of Pediatrics, University Hospital, Health Campus Immunology, Infectiology and Inflammation, Otto-von-Guericke-University , Magdeburg, Germany.
authors.forename: Mandy
authors.initials: M
authors.lastname: Pierau
authors.affiliation: Department of Pediatrics, University Hospital, Health Campus Immunology, Infectiology and Inflammation, Otto-von-Guericke-University , Magdeburg, Germany.
authors.forename: Monika C
authors.initials: MC
authors.lastname: Brunner-Weinzierl
keywords: CTL; IFNγ; IL-17; STATs; T cell differentiation; plasticity