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.

Analysis of the HLA-DR peptidome from human dendritic cells reveals high affinity repertoires and nonconventional pathways of peptide generation

“…When MoDCs were pulsed with Ag [23][24][25][26], most Ag-derived peptides were also HBs. A recent analysis of the HLA-DR1 peptidome of in vivo-enriched splenic DCs from transgenic mice also showed predicted high-affinity peptides to be the most abundant [18]; however, our prediction analysis of peptides from HLA-DR11, HLA-DR8, HLA-DR3, and HLA-DR4 lymphoblastoid cell lines [10][11][12]41] and rat insulinoma cells transfected with HLA-DR4 [11] showed a different distribution, where the intermediate-and low-affinity peptides represented between 40 and 60% of the total repertoire. Thus, preference for high-affinity peptides may be cell typedependent, which suggests that the intrinsic machinery of DCs may favor their generation and presentation, although a certain influence of the allele must be considered.…”

Human thymic epithelial primary cells produce exosomes carrying tissue‐restricted antigens

“…One intriguing question is how a small population of mTECs is able to school/purge the manifold larger population of developing thymocytes, especially since not every TRA is expressed in every mTEC 4 . One hypothesis among several is that exosomes could contribute as a mean of spreading antigens within the thymus 5 , 6 . Exosomes are nano‐sized membrane enclosed vesicles of endocytic origin, and are released into the extracellular space by cells when multivesicular bodies fuse with the cell plasma membrane.…”

“…4 One hypothesis among several is that exosomes could contribute as a mean of spreading antigens within the thymus. 5,6 Exosomes are nano-sized membrane enclosed vesicles of endocytic origin, and are released into the extracellular space by cells when multivesicular bodies fuse with the cell plasma membrane. Previous work have identified and characterized exosomes in murine 7 as well as human thymic tissue.…”

Thinking bedside at the bench: the NOD mouse model of T1DM

“…69–71 Recognition of antigens by autoreactive T cells is generally of low avidity and, therefore, seemingly minor differences in peptide binding between alleles have profound effects on responses to that antigen. For example, a single amino acid difference in the B chain of human insulin seems to account for the ability of porcine, but not human, insulin to prevent the development of diabetes mellitus in NOD mice.…”