Signal minus 1: a key factor in immunological tolerance to tissue-specific self antigens?
Recent data suggest that many autoreactive T cells, particularly to tissue-specific self antigens, can escape thymic deletion. The current dogma is that these autoreactive T cells are silenced by the failure of most tissues to provide co-stimulation (signal 2), antigen alone (signal 1) inducing T cell unresponsiveness. However, I propose that activation of autoreactive T cells frequently occurs but autodestruction by effector T cells is tightly regulated. This phenomenon is most evident with lymph node metastasizing tumour cells where the regional lymph node can mount a vigorous response to the invading tumour cells but tumour growth is unimpaired. I suggest that autodestruction is prevented by inhibitory receptors on T cells which recognize class I MHC structures on target cells. These receptors, which I propose deliver 'signal minus 1' to T cells, were recently described on NK cells and a subpopulation of peripheral T cells. They are also strikingly similar to a family of anti-self receptors that my laboratory described on murine T and B cells 15 years ago. In the 'signal minus 1' model, antigen-activated T cells acquire the inhibitory receptors when they become co-stimulation independent and gain the ability to exit lymphoid organs and enter non-lymphoid tissues. Thus, if autoreactive effector T cells encounter autoantigen in tissues they are functionally silenced by inhibitory receptor engagement and signal minus 1 delivery. In contrast, I propose that in response to intracellular infections, cells down-regulate expression of their ligands for inhibitory receptors. Such a model allows infected cells to be selectively eliminated by effector T cells. If correct, the model predicts that effector T cells, whether foreign-antigen- or autoantigen-specific, can selectively respond to infected cells. This apparent 'usefulness' of autoreactive T cells may explain their observed persistence even after an encounter with autoantigen. It is also suggested that signal minus 1 may silence autoreactive B cells specific for tissue-specific cell surface antigens and lack of signal minus 1 may partially explain the vigorous T cell response to allogeneic MHC. Finally, it is hypothesized that, in evolutionary terms, inhibition of autodestruction by the recognition of a 'self marker' and delivery of signal minus 1 is an ancient process which probably emerged in early metazoans.
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Division of Immunology and Cell Biology, John Curtin School of Medical Research, Australian National University, Canberra.
D000818:Animals; D001324:Autoantigens / Q000276:immunology*; D006801:Humans; D007519:Isoantigens / Q000276:immunology*; D009928:Organ Specificity / Q000276:immunology*; D017634:Self Tolerance; D015398:Signal Transduction / Q000276:immunology*
D001324:Autoantigens; D007519:Isoantigens