Degenerate T-cell receptor recognition, autoreactive cells, and the autoimmune response in multiple sclerosis

Multiple sclerosis (MS) is the leading cause of disability in the young adult population. While the immunopathogenetic mechanisms that drive the disease have been extensively studied, the autoantigens that trigger the chronic central nervous system inflammation are still not identified. Flexibility/ degeneracy of the T-cell receptor (TCR) in antigen recognition could have a physiological role in thymic selection and the development of comprehensive TCR repertoire and protection from infections. Here, the author explores the possibility that such flexibility/degeneracy may also play a role in the induction of autoimmune diseases. Major histocompatibility complex (MHC) class II alleles of the DR2 haplotype DR2a (DRB5*0101) and DR2b (DRB1*1501) are genes associated with an increased risk for MS in Caucasian populations. Peptide binding to the MHC molecule is a prerequisite for recognition by TCRs, whereby the CD4+ T-cell response is restricted by specific MHC class II DR molecules. To selectively expand and characterize DR2-restricted T-cells with degenerate TCR (TCR(deg)), the authors designed MHC class II DR2-anchored peptide mixtures, which preferentially bind to the DR2a and DR2b antigen-presenting molecules. Peptides in these mixtures have specific amino acids in the DR2 binding positions but have randomized amino acids at all other positions of the peptide. Due to the low concentration of individual peptides in these mixtures/libraries, the authors assume that only T-cells with TCR(deg) will proliferate in response to these mixtures. The authors have recently identified an increased DR2 restricted TCR(deg) T-cell frequency in MS patients in comparison to healthy controls, their cross-reactivity to myelin basic protein, and the secretion of proinflammatory cytokines, all of which suggest that these cells may play a role in the development of the autoimmune response in MS.