Potential Risks And Benefits Of Tcr Revision

As a tolerance mechanism, TCR revision appears to be a risky proposition. Reexpression of the recombinase machinery in mature peripheral T cells offers the potential for aberrant juxtaposition of cellular oncogenes and lymphocyte-specific promoters.27,28 Such genome instability can result in dysregulated cellular functions and transformation. It is not clear yet whether TCR revision increases the risk of oncogenesis. However a relationship between the increased frequency of TCRlowRAG+CD4+ peripheral T cells in ataxia telangiectasia and Nijmegen breakage syndrome patients and their frequent lymphoma-specific chromosomal translocations has been suggested.24 TCR revision may also serve to modulate T cell reactivity to superantigen-expressing bacterial or viral pathogens.26 Loss of superantigen reactivity could influence the outcome of an infection with such an organism.29-32 A further danger in TCR revision lies in the fact that by not eliminating the autoreactive cell outright, the individual exposes itself to the possibility of continued autoaggression. Although the endproduct of TCR revision is a population of cells that appears to be self tolerant, 20,21 it is unclear if the revision process itself is associated with stringent selection against overt self reactivity, as in the thymus during T cell maturation, or whether subsequent selection events in the lymphoid periphery are called into play to eliminate newly generated autoreactive T cells. Regardless of the means of selection, this secondary process is unlikely to be infallible. Why, then, would evolution select for such risk-taking behavior?

The surprisingly broad TCR repertoire that results from TCR revision is an obvious benefit to the individual faced with decreasing CD4+ T cell counts due to elimination of cells recognizing a self antigen it is unable to clear. The benefits of receptor revision may therefore outweigh the risks, although the age-dependency of TCR revision makes it likely these benefits are enjoyed most commonly by mice 5-6 months of age, well past the age of sexual maturity. One solution to this conundrum may be that the decision to upregulate RAG expression and undergo TCR revision is a byproduct of T cell maturation. During thymocyte development, RAG expression is maintained and TCR loci remain accessible to the recombinase until the proper signals are delivered into the cell through a functional TCR.33 In the absence of such a signal, TCR rearrangement continues.34 One of the first phenotypic changes apparent in cells undergoing TCR revision is the partial loss of TCR expression at the cell surface.20 In fact, following this TCRlow trait alone led to the isolation of RAG-expressing CD4+ T cells from human donors.23,24 Perhaps this downregulation, whether ligand-mediated or not, serves to decrease the basal level of signaling through the TCR, signaling that is thought to be key for T cell survival.35,36 The cell may interpret this loss of signaling capacity

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