Hypothesis on the origin of the strong alloreactivity.

The high proportion of alloreactive T lymphocytes and many of the available data on T cell receptors can be explained by one single hypothesis with four basic assumptions: A) The functional induction of T lineage cells in the thymus inherently causes a selection for V-regions that bind to major histocompatibility antigens (MHA). The type of MHA determines the functional pathway of the T cell. B) This process selects with the highest probability for binding sites with high affinity for the self-MHA, yet binding sites with high affinity for non-self-MHA and low affinity for self-MHA will also be selected with a low but finite probability. C) This positive selection for self-MHA binding V-regions is followed by a rigorous selection against self-reactive T cells during the subsequent thymic or post-thymic phase of tolerance induction. D) Most crucial for the hypothesis is, finally, the assumption that the second (negative) selection operates with a higher affinity threshold than the first (positive) selection. The negative selection thus spares T cell clones with low affinity for self-antigens. This provides a strong selective advantage for two major groups of cells, namely alloreactive cells most of which recognize nonself-MHA in complex with nonpolymorphic non-MHA determinants, and cells that recognize nonself-determinants in complex with self-MHA with different degrees of restriction. One of the predictions of this hypothesis is that the proportion of alloreactive cells is relatively small among the T lineage cells that leave the thymus but increases largely during the post-thymic development of the peripheral T cell pool. The hypothesis is not biased in respect to the underlying germ line repertoire of V genes, and is in fact compatible with the simple assumption that T and B cells use the same sets of V genes.