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

Falconer, Jane, Tibbitt, C, Stoop, J, van Eden, W, Robinson, JH and Hilkens, CMU (2016) Reduced TCR-dependent activation through citrullination of a T-cell epitope enhances Th17 development by disruption of the STAT3/5 balance. European Journal of Immunology, 46. pp. 1633-1643. ISSN 1521-4141

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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 na¨ıve 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.

Item Type: Article
Divisions: Faculty of Health Sciences and Wellbeing > School of Medicine
Depositing User: Jane Falconer
Date Deposited: 06 Sep 2019 13:04
Last Modified: 06 Sep 2019 13:07
URI: http://sure.sunderland.ac.uk/id/eprint/11084
ORCID for Jane Falconer: ORCID iD orcid.org/0000-0002-6601-7919

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