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

The third complementarity determining region (CDR3) is the most variable part of αβT 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 11 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 p 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.