The Repertoires of Peptides Presented by MHC-II in the Thymus and in Peripheral Tissue: A Clue for Autoimmunity?

Abstract

T-cell tolerance to self-antigens is established in the thymus through the recognition by developing thymocytes of self-peptide-MHC complexes and induced and maintained in the periphery. Efficient negative selection of auto-reactive T cells in the thymus is dependent on the in situ expression of both ubiquitous and tissue-restricted self-antigens and on the presentation of derived peptides. Weak or inadequate intrathymic expression of self-antigens increases the risk to generate an autoimmune-prone T-cell repertoire. Indeed, even small changes of self-antigen expression in the thymus affect negative selection and increase the predisposition to autoimmunity. Together with other mechanisms, tolerance is maintained in the peripheral lymphoid organs via the recognition by mature T cells of a similar set of self-peptides in homeostatic conditions. However, non-lymphoid peripheral tissue, where organ-specific autoimmunity takes place, often have differential functional processes that may lead to the generation of epitopes that are absent or non-presented in the thymus. These putative differences between peptides presented by MHC molecules in the thymus and in peripheral tissues might be a major key to the initiation and maintenance of autoimmune conditions.

Keywords: MHC-II; human; peptide repertoire; peripheral tissues; thymus.

Figure 1

Thymus and peripheral tissue mechanisms involved in antigen processing. (A) In thymus, tissue-restricted antigens (TRAs) are expressed by medullary epithelial cells (mTECs) for negative selection. Secretory TRAs are processed by self-proteases and peptides (orange squares and red triangles) are loaded onto MHC-II molecules once exocytic vesicles reach the MIIC compartment. Peptide exchange is mediated by HLA-DM. Macroautophagy permits the access of cytosolic TRAs and other proteins into the MIIC compartment so their processing and presentation via MHC-II can take place. Besides their own proteome, thymus dendritic cells (DC) are expected to present antigens via the uptake of apoptotic thymocytes and mTECs, exosomes delivered by mTECs and other extracellular material. Thymus-specific and conventional proteases generate high affinity peptides from a wide range of self-proteins, thus favoring their presentation in competition with low-affinity peptides. (B) In peripheral tissues, specific proteases may be essential for peptide generation. A protein can generate peptides for MHC-II in the secretory pathway. Tissue-specific post-translational modifications may result in modified antigenic peptides (orange squares from thymus are represented as green squares in periphery) or even prevent the generation of some peptides. Once in the extracellular environment, proteases could partially degrade the protein into smaller fragments (yellow circles) that would be potential binders for MHC-II molecules. In some cases protein storage outside the cells (e.g., thyroglobulin in thyroid colloid) is followed by protein turn-over into the cells. Proteins or their cleavage products contained in endosomes can be processed again in the MIIC compartment to generate MHC-II ligands. During inflammation, infiltrating DCs can uptake the antigenic proteins or their fragments for processing with their specific proteases. They can also phagocyte apoptotic epithelial cells. Compared with thymus, events in periphery may result in a set of presented peptides that were not used in negative selection. Lack of competition with high affinity peptides and low or absent expression of HLA-DM may result in the presentation of peptides with low affinity for MHC-II molecules.