Quantitative Considerations of T‐Cell Activation and Self Tolerance

Abstract

We have reviewed evidence for the hypothesis that T-cell activation by antigen is an all or none process which is triggered when signal strength exceeds a certain threshold. Signal is generated by multivalent interaction between T-cell antigen receptors (TCR) and antigenic epitopes on the surface of antigen-presenting cells (APC) or target cells. Therefore total signal strength (Stot) will depend upon the concentration of TCR (and other accessory molecules that bind to cell surface ligands, e.g. CD4 and CD8) on T cells, the concentration of antigen on APC or targets and the affinity of interaction between receptors (a broad term incorporating TCR plus CD4 and CD8) and antigen. This hypothesis means that T-cell self tolerance is quantitatively determined by self-antigen concentrations on cell surfaces. Implications for a variety of immunological phenomenona are reviewed.

The outer surface lipoprotein OspA of Borrelia burgdorferi provides co‐stimulatory signals to normal human peripheral CD4+ and CD8+ T lymphocytes

“…All these cytokines have been shown profoundly to affect vascular endothelium and to promote extravasation of leukocytes into effected tissues [32-341. In addition, IFN-y may induce Tcell-mediated pathology as a consequence of breakdown of self tolerance by up-regulating cell surface expression of MHC antigens [35]. The description of such autoreactive T cells from patients with Lyme disease supports this hypothesis [16].…”

Murine candidiasis: Susceptibility is associated with the induction of T cell‐mediated, strain‐specific autoreactivity

“…In the event of a subsequent infection, not only would Candida antigens tend to activate these cells, but they would also be exposed to a higher level of expression of Class II MHC antigens induced as a consequence ofthe infection (14). This latter, in particular, may lead to a breakdown in the mechanisms controlling the auto-reactive cells (15). In vitro culture has been shown to permit the expression of anti-self reactivity in other systems in which peripheral suppression has been inferred to be operational (16); however, suppressor cells can also be induced in the absence of significant proliferation (17).…”

Patients, Pathogens, and Protective Immunity: The Relevance of Virus-Induced Alloreactivity in Transplantation

“…While the specificity of TCR recognition is often emphasized as a hallmark of adaptive immunity, if each TCR could recognize only a single MHC-peptide complex, then the actual repertoire would be incapable of expressing enough unique TCRs to cover the entire "antigenic universe" (10). Experimental evidence indicates that, in fact, TCRs show a considerable degree of degeneracy in their recognition of MHC-peptide complexes (11)(12)(13). Similarly, mathematical modeling estimates suggest that one TCR might recognize Ͼ10 6 distinct peptide/MHC complexes (10).…”