The inability to process a self-peptide allows autoreactive T cells to escape tolerance.

Abstract

SummaryIt is now clear that antigen presenting cells (APCs) do not present all the possible peptides of self-proteins to the immune system. What then, is the fate oft cells specific for those self-peptides that escape processing? In this study, the COOH-terminal peptide (residues 81-104) of self cytochrome c (cyt c) elicited strong autoimmune T cells, as well as autoantibodies specific for this immunogen. These T cells did not respond to stimulation with the whole self cyt c molecule, demonstrating that APCs cannot process and present the self 81-104 peptide. Whereas mice were unresponsive to immunization with the whole mouse cyt c molecule, the mouse 81-104 fragment together with the whole self-molecule induced and amplified the autoimmune T cell response to sites within the 1-80 peptide. T cells that never contact the relevant self-peptide are functionally ignorant. They do not become tolerized or deleted, nor do they normally participate in immune responses to the native whole self-protein, since APCs cannot present the 81-104 peptide.

Activated Self-MHC-Reactive T Cells Have the Cytokine Phenotype of Th3/T Regulatory Cell 1 T Cells

“…This indicates that T cells with self-reactivity presumably reacting to an as yet undefined cohort of self-Ags in the MHC groove are a normal part of the T cell population (27)(28)(29)(30) and are unintentionally expanded during ordinary Ag-driven T cell priming. However, the present studies indicate that these T cells are very different from the exogenous Ag-specific T cells with which they codevelop, in that they have the properties of regulatory T cells (Th3 T cells or Tr1 T cells) that have been shown in previous studies to regulate autoimmune inflammation (11,12,17).…”

Mimicry peptides of human PDC-E2 163-176 peptide, the immunodominant T-cell epitope of primary biliary cirrhosis

“…[2][3][4][5][6][7] However, in most cases, these autoreactive T cells in healthy subjects are suppressed to prevent the induction of autoimmune diseases. This can be explained by theories of T-cell anergy, 22 T-cell ignorance, [23][24][25] active suppression by regulatory T cells, 26,27 or by the lack of sufficient stimulation of self-reactive peptides. Several mechanisms may explain the activation and clonal expansion of autoreactive T cells, including antigenic stimulation of molecular mimicry peptides derived from viral, bacterial, or other environmental nonself antigen; aberrant or increased expression of self-antigens; or cryptic autoepitopes accompanied by the expression of costimulatory molecules, bacterial or viral superantigens that trigger T cells bearing particular T-cell receptor β segments, and cytokine modulation, including IL-2 locally produced in response to various environmental nonself antigen.…”

Interleukin-10–mediated regulatory T-cell responses to epitopes on a human red blood cell autoantigen

“…The data also support the belief that the pathogenic Th1 response in diseases such as AIHA 2,28,46 targets epitopes that are normally cryptic or subdominant. 48,49 Since the size of the IL-10 response to the RhD protein varies with the number of sequences that elicit IL-10, we now hypothesize that the progress of disease is determined by changes in antigen presentation that alter the relative abundance with which the different sets of epitopes are processed and presented.…”