Targeting T lymphocytes for immune monitoring and intervention in autoimmune diabetes

Recognition of a peptide-MHC complex by the T cell receptor (TCR) is a key interaction that initiates T lymphocyte activation or silencing during an immune response. Fluorochrome-labeled recombinant MHC class II-peptide reagents function as soluble mimetics of this interaction, bind to their specific TCR, and allow for detection of antigen-specific CD4+ T cells. These reagents are now under scrutiny for "immune staging" of patients at risk of type 1 diabetes, in an effort to diagnose islet autoimmunity early enough to block immune-mediated beta cell destruction. Several issues are currently being addressed to improve the performance of these T cell assays: enrichment steps for better sensitivity, multiplexing of several islet epitopes, simultaneous monitoring of CD4+ and CD8+ responses, detection of low avidity T cells, combination of quantitative (number of positive cells) and qualitative (cytokine secretion, naive/memory phenotype) readouts. CD4+ T cells are key effectors of autoimmunity, and these MHC class II peptide reagents, through their signaling properties, might also provide therapeutics to block the autoimmune process at its onset, analogous to the use of OKT3gammao1(AlaAla) anti-CD3 antibody but in an antigen-specific fashion. The aim of such therapeutics is to potentiate different physiological control mechanisms to restore immune tolerance. Mechanisms initiated by this pathway may be capable of triggering elimination of pathogenic T cells through antigen-specific apoptosis and anergy, combined with the induction of regulatory T cells with broad suppressive function.