title: Reduced TCR-dependent activation through citrullination of a T-cell epitope enhances Th17 development by disruption of the STAT3/5 balance.
abstract: Citrullination is a post-translational modification of arginine that commonly occurs in inflammatory tissues. Because T-cell receptor (TCR) signal quantity and quality can regulate T-cell differentiation, citrullination within a T-cell epitope has potential implications for T-cell effector function. Here, we investigated how citrullination of an immunedominant T-cell epitope affected Th17 development. Murine naïve CD4(+) T cells with a transgenic TCR recognising p89-103 of the G1 domain of aggrecan (agg) were co-cultured with syngeneic bone marrow-derived dendritic cells (BMDC) presenting the native or citrullinated peptides. In the presence of pro-Th17 cytokines, the peptide citrullinated on residue 93 (R93Cit) significantly enhanced Th17 development whilst impairing the Th2 response, compared to the native peptide. T cells responding to R93Cit produced less IL-2, expressed lower levels of the IL-2 receptor subunit CD25, and showed reduced STAT5 phosphorylation, whilst STAT3 activation was unaltered. IL-2 blockade in native p89-103-primed T cells enhanced the phosphorylated STAT3/STAT5 ratio, and concomitantly enhanced Th17 development. Our data illustrate how a post-translational modification of a TCR contact point may promote Th17 development by altering the balance between STAT5 and STAT3 activation in responding T cells, and provide new insight into how protein citrullination may influence effector Th-cell development in inflammatory disorders.
authors.affiliation: Musculoskeletal Research Group, Institute of Cellular Medicine, Newcastle University, U.K.
authors.forename: Christopher
authors.initials: C
authors.lastname: Tibbitt
authors.affiliation: Rheumatology Research Group, School of Immunity and Infection, University of Birmingham, U.K.|Arthritis Research UK Rheumatoid Arthritis Pathogenesis Centre of Excellence (RACE), U.K.
authors.forename: Jane
authors.initials: J
authors.lastname: Falconer
authors.affiliation: Department of Rheumatology, Leiden University, The Netherlands.
authors.forename: Jeroen
authors.initials: J
authors.lastname: Stoop
authors.affiliation: Institute of Infectious Diseases and Immunology, Utrecht University, The Netherlands.
authors.forename: Willem
authors.initials: W
authors.lastname: van Eden
authors.affiliation: Musculoskeletal Research Group, Institute of Cellular Medicine, Newcastle University, U.K.
authors.forename: John H
authors.initials: JH
authors.lastname: Robinson
authors.affiliation: Musculoskeletal Research Group, Institute of Cellular Medicine, Newcastle University, U.K.|Arthritis Research UK Rheumatoid Arthritis Pathogenesis Centre of Excellence (RACE), U.K.
authors.forename: Catharien M U
authors.initials: CM
authors.lastname: Hilkens
mesh_terms: D000818:Animals; D016207:Cytokines / Q000096:biosynthesis; D018984:Epitopes, T-Lymphocyte / Q000276:immunology* / Q000378:metabolism; D008213:Lymphocyte Activation / Q000276:immunology*; D051379:Mice; D008822:Mice, Transgenic; D010455:Peptides / Q000276:immunology / Q000378:metabolism; D011485:Protein Binding; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D050799:STAT5 Transcription Factor / Q000378:metabolism*; D058504:Th17 Cells / Q000276:immunology* / Q000378:metabolism*; D018418:Th2 Cells / Q000276:immunology / Q000378:metabolism
chemical_list: D016207:Cytokines; D018984:Epitopes, T-Lymphocyte; D010455:Peptides; D011948:Receptors, Antigen, T-Cell; D050796:STAT3 Transcription Factor; D050799:STAT5 Transcription Factor
keywords: Cellular activation; Citrullination; STAT3; STAT5; T helper cells; TCR; Th17 cells