title: Priming with very low-affinity peptide ligands gives rise to CD8(+) T-cell effectors with enhanced function but with greater susceptibility to transforming growth factor (TGF)β-mediated suppression.
abstract: While the effects of TCR affinity and TGFβ on CD8(+) T-cell function have been studied individually, the manner in which TCR affinity dictates susceptibility to TGFβ-mediated suppression remains unknown. To address this issue, we utilized OVA altered peptide ligands (APLs) of different affinities in the OT-I model. We demonstrate that while decreased TCR ligand affinity initially results in weakened responses, such interactions prime the resultant effector cells to respond more strongly to cognate antigen upon secondary exposure. Despite this, responses by CD8(+) T cells primed with lower-affinity TCR ligands are more effectively regulated by TGFβ. Susceptibility to TGFβ-mediated suppression is associated with downregulation of RGS3, a recently recognized negative regulator of TGFβ signaling, but not expression of TGFβ receptors I/II. These results suggest a novel tolerance mechanism whereby CD8(+) T cells are discriminately regulated by TGFβ according to the affinity of the ligand on which they were initially primed. In addition, because of the major role played by TGFβ in tumor-induced immune suppression, these results identify the affinity of the priming ligand as a primary concern in CD8(+) T-cell-mediated cancer immunotherapeutic strategies.
authors.affiliation: Department of Surgery, Committee on Immunology, The University of Chicago, Surgery Brain Research Building, IL 60637, USA.
authors.forename: Jeremy A
authors.initials: JA
authors.lastname: O'Sullivan
authors.forename: Andrew
authors.initials: A
authors.lastname: Zloza
authors.forename: Frederick J
authors.initials: FJ
authors.lastname: Kohlhapp
authors.forename: Tamson V
authors.initials: TV
authors.lastname: Moore
authors.forename: Andrew T
authors.initials: AT
authors.lastname: Lacek
authors.forename: Nickolai O
authors.initials: NO
authors.lastname: Dulin
authors.forename: José A
authors.initials: JA
authors.lastname: Guevara-Patiño
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D015536:Down-Regulation; D019204:GTP-Binding Proteins / Q000096:biosynthesis / Q000276:immunology; D020690:GTPase-Activating Proteins / Q000096:biosynthesis / Q000276:immunology; D006801:Humans; D008024:Ligands; D051379:Mice; D008810:Mice, Inbred C57BL; D009842:Oligopeptides / Q000276:immunology* / Q000494:pharmacology; D020710:RGS Proteins; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D016212:Transforming Growth Factor beta / Q000276:immunology* / Q000378:metabolism / Q000494:pharmacology
chemical_list: D020690:GTPase-Activating Proteins; D008024:Ligands; D009842:Oligopeptides; D020710:RGS Proteins; C485898:RGS3 protein, human; D016212:Transforming Growth Factor beta; D019204:GTP-Binding Proteins