T cells

As we have already seen, during T cell development in the thymus the process of negative selection leads to the deletion of thymocytes whose T cell receptors have 'high affinity' for self. One aspect we did not consider was what other parameters influenced this selection event. The only one we need to discuss is antigen concentration. Remember that in the context of T cells, antigen means the complex of specific peptide and MHC so the density of any given peptide-MHC complex is determined by the abundance of the peptide and it's affinity for the particular MHC allele. The number of molecules of any given peptide-MHC complex on the surface of a thymic antigen presenting cell probably varies from 1-50,000. We can imagine that if there is only a mean of 1 complex/cell then even the highest affinity T cells might fail to be deleted whereas for the most abundant peptide-MHC complexes quite low affinity T cells would be deleted. Thus we would predict an inverse relationship between the threshold affinity of TCR for peptide-MHC required to produce deletion and the abundance of that peptide-MHC complex. Using transgenic mice and organ culture techniques it has been possible to provide evidence for this hypothesis.

Added Value
Almost any other parameter which affects the overall strength of interaction between a clone of thymocytes and the thymic antigen presenting cell also affects the positive/negative selection decision. Thus the concentration (density) of TCR and of CD4 or CD8 also influences this reaction. One mechanism of escape for 'autoreactive' cells into the periphery that has been seen in TCR transgenic mice is downregulation of the T cell receptor, co-receptor or both.

B cells

During B cell development in the bone marrow when the complete antigen receptor (IgM) is first expressed on 'immature' B cells if those cells encounter their target antigen in a form which can cross-link their sIgM then such cells are programmed to die (deleted from the repertoire). This was discovered many years ago when it was shown that injection of a polyclonal anti-IgM from birth prevented the development of B cells, resulting in a 'B-less' mouse. The requirement for crosslinking means that the antigen has to be polyvalent, the most obvious example of this being cell-surface molecules. This has been directly demonstrated by using transgenic mice expressing rearranged Immunoglobulin genes specific for natural or artificial membrane bound molecules. Presumably other multivalent self antigens to which immature B cells are exposed also induce deletion of self reactive cells.

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