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Reduced TCR-dependent activation through citrullination of a T-cell epitope enhances Th17 development by disruption of the STAT3/5 balance

Lookup NU author(s): Chris Tibbitt, Dr Jane Falconer, Dr Jeroen Stoop, Emeritus Professor John Robinson, Professor Catharien HilkensORCiD

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).

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.

Publication metadata

Author(s): Tibbitt C, Falconer J, Stoop J, vanEden W, Robinson JH, Hilkens CMU

Publication type: Article

Publication status: Published

Journal: European Journal of Immunology

Year: 2016

Volume: 46

Issue: 7

Pages: 1633-1643

Print publication date: 01/07/2016

Online publication date: 13/05/2016

Acceptance date: 09/05/2016

Date deposited: 09/06/2016

ISSN (print): 0014-2980

ISSN (electronic): 1521-4141

Publisher: Wiley

URL: http://dx.doi.org/10.1002/eji.201546217

DOI: 10.1002/eji.201546217

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