Preferential Vβ gene usage and lack of junctional sequence conservation among human T cell receptors specific for a tetanus toxln-derived peptide: Evidence for a dominant role of a germline-encoded V region in antigen/major histocompatibility complex recognition

To investigate the structural and genetic basis of the T cell response to defined peptide/major histocompatibility (MHC) class II complexes in humans, we established a large panel of T cell clones (61) from donors of different HLA-DR haplotypes and reactive with a tetanus toxin-derived peptide (tt830-844) recognized in association with most DR molecules (universal peptide). By using a bacterial enterotoxin-based proliferation assay and cDNA sequencing, we found preferential use of a particular Vβ region gene segment, Vβ2.1, in three of the individuals studied (64%, n = 58), irrespective of whether the peptide was presented by the DR6wcI, DR4w4, or DRw11.1 and DRw11.2 alleles, demonstrating that shared MHC class II antigens are not required for shared Vβ gene use by T cell receptors (TCRs) specific for this peptide. Vα gene use was more heterogeneous, with at least seven different Vα segments derived from five distinct families encoding ot chains able to pair with Vβ2.1 chains to form a tt830-844/DR-specific binding site. Several cases were found of dories restricted to different DR alleles that expressed identical Vβ and (or very closely related) Vα gene segments and that differed only in their junctional sequences. Thus, changes in the putative complementary determining region 3 (CDR3) of the TCR may, in certain cases, alter MHC specificity and maintain peptide reactivity. Finally, in contrast to what has been observed in other defined peptide/MHC systems, a striking heterogeneity was found in the junctional regions of both α and β chains, even for TCRs with identical Vα and/or Vβ gene segments and the same restriction. Among 14 anti-tt830-844 clones using the Vβ2.1 gene segment, 14 unique Vβ-D-Jβ junctions were found, with no evident conservation in length and/or amino acid composition. One interpretation for this apparent lack of coselection of specific junctional sequences in the context of a common V element, Vβ2.1, is that this V region plays a dominant role in the recognition of the tt830-844/DR complex. © 1992, Rockefeller University Press., All rights reserved.