Is Citrullination Required for the Presence of Restricted Clonotypes Reacting With Type II Collagen? Comment on the Article by Chemin et al

We read with great interest the recently accepted article by Chemin et al (1), in which they identified and functionally characterized citrullinated (Cit) collagen type II (CII)-specific T cell epitopes relevant to RA. Chemin and coll. enrolled a cohort of 15 HLA-DRB1*10:01 positive RA patients and healthy donors, stimulated with candidate CII peptides, demonstrating that the citrullination process is able to generate T cells specific for Cit-epitopes from CII. Particularly interesting is their report of the influence of citrulline residues on presentation and recognition of peptides by T cells. Furthermore the authors show also that amino acids not directly contacting the binding groove affect T cell recognition and somehow the peptide interaction with the HLA pocket. We studied in depth this interaction using a computational modelling where we explored the three-dimensional model for the ternary complex TCR-Vbeta, not citrullinated CII 261-273 and HLA-DR4 (1). The generation of the three-dimensional structure of TCR/DR4-collagen complex defined a roadmap that led to the identifications of small-molecule inhibitors able to block proliferation of CII261-273/HLA-DR4 specific T cells (2). These molecules can prove to be a valid starting point for the discovery of new and more potent derivatives able to disrupt protein-protein interaction between TCR and collagen/HLA-DR4 complex, blocking T cells proliferation through a mechanism of action that differs to those of therapeutic agents used currently against RA. In this context it is important to define the role of HLADRB1*10 in the pathogenesis of RA, in particular because it represents a very small portion in general population (less then 10%) and in particular RA population. Peculiar interest resides in the interaction of different HLA-DRB1 alleles, as we suggested in a recently published work (3); we demonstrated that shared, autoreactive, CII261-273 specific TRBV25-TRBJ2.2+ T cells could be selected on the background