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.