T cell receptor germline gene segments and HLA haplotypes control the length of the CDR3 of human T cell receptor beta chains.

The third complementarity determining region (CDR3) is the most variable part of alpha beta T cell receptors (TCR) and represents the putative antigen contacting site. To identify parameters determining the structural diversity of the CDR3 region, the CDR3 length distributions of 66 BV-J combinations in peripheral CD4+ T cells (6 BV and ll BJ gene segments) of 12 unrelated individuals were analyzed. The median CDR3 length ranged from 8 to 12.5 amino acids and was partially determined by the usage of the BV and BJ gene segment. Beyond the influence of germline-encoded TCR gene segments, donors expressed an individual pattern of preferred CDR3 size classes. To identify mechanisms determining this individual pattern, 17 first-degree relatives from five families were studied. CDR3 length profiles were shared by some but not all relatives. Sharing of CDR3 length profiles correlated with the inheritance of both HLA-DR haplotypes. These data suggest that the length of the TCR beta chain is selected and that restrictions on the diversity of the CDR3 length are imposed by germline-encoded TCR gene segments as well as by major histocompatibility complex-dependent mechanisms.