An additional hypervariable region encoded by V gene segments occurs in Tcr V beta at a location compatible with its involvement in Tcr active site--a general model for alloreactivity.

The number of V alpha and V beta sequences of T cell receptors now available allows a meaningful analysis of their variability profiles. Variability plots were derived using a modified form of Wu and Kabat's algorithm: variability is not computed as a proportion of the number of different residues occurring at a position, but rather proportionally to the physicochemical differences between the different residues. Results show that the classical hypervariable regions occurring in immunoglobulins also occur in T cell receptors at equivalent positions. Contrary to immunoglobulins the framework of Tcr V regions displays many relatively variable regions and positions. This phenomenon can be connected with the genetic organization of V genes of T cell receptors which seem to avoid any framework homogenization and the resulting gene conversion. More importantly an additional hypervariable region was detected in V beta but not in V alpha. This fourth hypervariable region is located between the second and the D hypervariable CDR. The predicted three-dimensional location of this additional hypervariable region is compatible with a possible role in antigen recognition and therefore also in positive and/or negative selection. Furthermore our data suggest that this fourth hypervariable region is involved in the recognition of superantigens like bacterial enterotoxins. Indeed this additional hypervariable region is not detected when variability is derived using an alignment of the V beta subgroups stimulated by one toxin of S. aureus. Finally we propose a new and simple molecular model to explain alloreactivity as crossreactivity between the universe of shapes (isomers of conformation) of different MHC haplotypes.