Specificity, degeneracy, and molecular mimicry in antigen recognition by HLA-Class II restricted T cell receptors: implications for clinical medicine

Abstract

In humans, increased susceptibility to specific autoimmune diseases is closely associated with specific HLA-class II alleles. CD4+ T cells that recognize short self-peptides in the context of HLA-class II molecules via their T cell receptor (TCR) are considered to mediate the central role of pathogenesis in autoimmunity. Although both self- and nonself-peptides are presented on HLA-class II molecules under physiological conditions, several mechanisms exist to avoid the T cell response to the self-peptide/HLA-class II complex. One of the mechanisms that account for the breakdown in immune tolerance is cross-recognition by TCR between a pathogen-derived antigen and a host antigen (molecular mimicry theory). Epidemiological studies have indicated that a number of autoimmune diseases are developed or exacerbated after infections. Therefore, elucidating the recognition nature of HLA-class II restricted TCR in detail is necessary in order to understand disease processes. A large body of evidence indicates that T cell recognition is highly degenerate, and many different peptides can activate an individual T cell. Degeneracy of TCR recognition also can appear in various physiological outcomes, ranging from full activation to strong antagonism. Here, we review the clinical implications of our findings on T cell recognition, as well as a new direction of future applications for analyses in molecular mimicry. We also describe the latest developments in methods of mapping TCR epitopes for CD4+ T cells using a peptide epitope expression library generated in the class II-associated invariant chain peptide substituted invariant chain gene format.