CD28-Dependent CTLA-4 Expression Fine-Tunes the Activation of Human Th17 Cells

• Type of Material: Article
• Authors: Scott Krummey, Emory University; Christina R. Hartigan, Emory University; Danya Liu, Emory University; Mandy Ford, Emory University
• Language: English
• Date: 2020-04-24
• Publisher: CELL PRESS
• Publication Version: Final Published Version
• Copyright Statement: © 2020 The Authors Molecular Mechanism of Behavior; Immunology; Immune Response
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1016/j.isci.2020.100912
• Title of Journal or Parent Work: ISCIENCE
• Volume: 23
• Issue: 4
• Start Page: 100912
• End Page: 100912
• Grant/Funding Information: This work was supported by the Roche Organ Transplant Research Foundation (M.L.F.), R01 AI104699 (M.L.F.), K99 AI146271 (S.M.K.), T32 AI007610-11 (S.M.K.), T32 GM08169-23 (S.M.K.), T32A1070081 (S.M.K.), F30 DK098928-01 (S.M.K.), and the Transplant Immunology Research Network (S.M.K.). Molecular cloning was generously provided by Dr. Oskar Laur and the Emory Integrated Genomics Core, which is subsidized by the Emory University School of Medicine and is one of the Emory Integrated Core Facilities. Additional support was provided by the Georgia Clinical & Translational Science Alliance of the National Institutes of Health (UL1TR002378).
• Keywords: Science & Technology - Other Topics; COSTIMULATION; Multidisciplinary Sciences; ABATACEPT; SIGNALS; INHIBITORS; DIFFERENTIATION; CD28; MECHANISMS; T-CELLS; Science & Technology; FOXO TRANSCRIPTION FACTORS; DISEASE
• Research Categories: Biology, Cell; Health Sciences, Pathology

Abstract

Previous work has demonstrated that Th17 memory cells but not Th1 cells are resistant to CD28/CTLA-4 blockade with CTLA-4 Ig, leading us to investigate the individual roles of the CD28 and CTLA-4 cosignaling pathways on Th1 versus Th17 cells. We found that selective CD28 blockade with a domain antibody (dAb) inhibited Th1 cells but surprisingly augmented Th17 responses. CD28 agonism resulted in a profound increase in CTLA-4 expression in Th17 cells as compared with Th1 cells. Consistent with these findings, inhibition of the CD28 signaling protein AKT revealed that CTLA-4 expression on Th17 cells was more significantly reduced by AKT inhibition relative to CTLA-4 expression on Th17 cells. Finally, we found that FOXO1 and FOXO3 overexpression restrained high expression of CTLA-4 on Th17 cells but not Th1 cells. This study demonstrates that the heterogeneity of the CD4+ T cell compartment has implications for the immunomodulation of pathologic T cell responses.