Immunological surveillance and graft rejection

Holes in the TCR repertoire resulting from the need to maintain self-tolerance may not normally constitute a problem for the specific host response to viruses or bacteria, as any pathogen is likely to incorporate a great many nonself peptides that can potentially associate with one of the self MHC glycoproteins. This thinking can legitimately be extended to the B cell lymphoma induced by Epstein-Barr virus which, at least for Caucasians, may normally be held in check by T cells. However, the effectiveness of such surveillance for tumors that are not induced by viruses is likely to be very much constrained, especially as there is no obvious reason why a particular oncogenic change should be characterized by the expression of novel peptides that bind to MHC molecules, unless the level of some poorly expressed gene is upregulated to a point where sufficient peptides from that protein are generated and available to bind MHC molecules. Also, the selection pressure exerted by immune T cells on tumors that are immunogenic can lead to the emergence of variants that no longer express the target MHC class I molecule. Further, to initiate an immune response the responding T cell must receive not only a signal from a cognate TCR/MHC interaction, but also costimu-latory signals from accessory molecules expressed on the tumor cell. Gene therapy studies have suggested that strategies to express MHC and/or costimulatory molecules on tumor cells may help to initiate a tumor-specific immune response in vivo.

The account so far has concentrated on the part played by the MHC in the monitoring of self by T lymphocytes, the phenomenon known as MHC restriction. However, the MHC is named for, and was historically defined by, the phenomenon of allo-reactivity that is the central feature of graft rejection. Current thinking is that the high frequency of T cells (>1:1000 spleen celts in the mouse) specific for any-foreign MHC glycoprotein reflects that a TCR which recognizes a particular self-derived MHC-peptide complex will also bind to one or other nonself MHC molecules (alloantigens). However, this does not necessarily mean that alloreactivity is simply an epi-phenomenon of the self-surveillance mechanism. It is possible that the fine tuning of host response represented by the thymic T cell-MHC interactions has derived in evolutionary time from a much more primitive mechanism analogous to that operating, for instance, to prevent one colony of corals from parasitizing another. The precursors of the TCR genes are likely to have been a considerably less diverse set of genes encoding cell interaction molecules.

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