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Low-Affinity Major Histocompatibility Complex–Binding Peptides in Type 1 Diabetes

¹ Benaroya Research Institute, Virginia Mason Medical Center, Seattle, Washington
² Department of Immunology, University of Washington, Seattle, Washington

Corresponding author: William W. Kwok, bkwok@benaroyaresearch.org

The first 20% of the full text of this article appears below.

Type 1 diabetes is characterized by T-cell–mediated destruction of insulin-producing β-cells. The strong association between autoimmune diabetes and certain susceptible major histocompatibility complex (MHC) class II alleles suggests that T-cell activation by self-peptides presented via these MHC class II alleles plays a critical role in the disorder's pathogenesis. A diverse repertoire of T-cells is generated in the thymus, first through positive selection on MHC and self-peptide within the thymic cortex. This process requires adequate peptide presentation through interactions with MHC and sufficient T-cell receptor (TCR) signaling through the TCR/MHC/self-peptide complex (Fig. 1). As such, all T-cells in normal physiology are intrinsically self-reactive. However, subsequent negative selection of self-reactive T-cells in the thymic medulla should lead to clonal deletion for TCRs that recognize self-peptide/MHC with high affinity. Although some self-reactive, high-avidity T-cells do escape into peripheral circulation, suboptimal recognition of MHC/self-peptide by the TCRs may be required for T-cells to escape tolerance mechanisms. This idea is supported by experimental observations that the affinity of TCRs for MHC/self-peptide is generally lower than that for MHC/foreign peptide and that the interactions of autoreactive TCRs to MHC/self-peptide appear to be less extensive than to foreign peptide (1,2). In light of the opposing mechanisms of positive and negative selection, fundamental questions remain regarding the affinity of TCR/MHC/self-peptide interactions that give rise to autoreactive T-cell responses.

View larger version (14K):   FIG. 1. The T-cell repertoire is determined by positive and negative selection. T-cells with . . . [Full Text of this Article]

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