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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

Tibbitt et al., Eur J Immunol. (2016) - PMID: 27173727

Product(s) used in this publication:  Custom Peptide Synthesis

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.

© 2016 The Authors. European Journal of Immunology published by WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

KEYWORDS:

Cellular activation; Citrullination; STAT3; STAT5; T helper cells; TCR; Th17 cells

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