title: CD8 co-receptor promotes susceptibility of CD8+ T cells to transforming growth factor-β (TGF-β)-mediated suppression.
abstract: CD8+ T cell function depends on a finely orchestrated balance of activation/suppression signals. While the stimulatory role of the CD8 co-receptor and pleiotropic capabilities of TGF-β have been studied individually, the influence of CD8 co-receptor on TGF-β function in CD8+ T cells is unknown. Here, we show that while CD8 enhances T cell activation, it also enhances susceptibility to TGF-β-mediated immune suppression. Using Jurkat cells expressing a full-length, truncated or no αβCD8 molecule, we demonstrate that cells expressing full-length αβCD8 were highly susceptible, αβCD8-truncated cells were partially susceptible, and CD8-deficient cells were completely resistant to suppression by TGF-β. Additionally, we determined that inhibition of Lck rendered mouse CD8+ T cells highly resistant to TGF-β suppression. Resistance was not associated with TGF-β receptor expression but did correlate with decreased Smad3 and increased Smad7 levels. These findings highlight a previously unrecognized third role for CD8 co-receptor which appears to prepare activated CD8+ T cells for response to TGF-β. Based on the important role which TGF-β-mediated suppression plays in tumor immunology, these findings unveil necessary considerations in formulation of CD8+ T cell-related cancer immunotherapy strategies.
authors.affiliation: Department of Surgery, Committee on Immunology, The University of Chicago, 5841 S. Maryland Avenue, Chicago, IL 60637, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Zloza
authors.forename: Michael C
authors.initials: MC
authors.lastname: Jagoda
authors.forename: Gretchen E
authors.initials: GE
authors.lastname: Lyons
authors.forename: Michael C
authors.initials: MC
authors.lastname: Graves
authors.forename: Frederick J
authors.initials: FJ
authors.lastname: Kohlhapp
authors.forename: Jeremy A
authors.initials: JA
authors.lastname: O'Sullivan
authors.forename: Andrew T
authors.initials: AT
authors.lastname: Lacek
authors.forename: Michael I
authors.initials: MI
authors.lastname: Nishimura
authors.forename: José A
authors.initials: JA
authors.lastname: Guevara-Patiño
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D016827:CD8 Antigens / Q000096:biosynthesis / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D006801:Humans; D007108:Immune Tolerance / Q000276:immunology*; D019169:Jurkat Cells; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D051379:Mice; D008810:Mice, Inbred C57BL; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000378:metabolism; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology; D051785:Smad Proteins / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000276:immunology*
chemical_list: D000911:Antibodies, Monoclonal; D016827:CD8 Antigens; D016693:Receptors, Antigen, T-Cell, alpha-beta; D018125:Receptors, Transforming Growth Factor beta; D051785:Smad Proteins; D016212:Transforming Growth Factor beta; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck)