Many different Vbeta CDR3s can reveal the inherent MHC reactivity of germline-encoded TCR V regions.
We have hypothesized that in the prenegative selection TCR repertoire, many somatically generated complementary-determining region (CDR) 3 loops combine with evolutionarily selected germline Valpha/Vbeta CDR1/CDR2 loops to create highly MHC/peptide cross-reactive T cells that are subsequently deleted by negative selection. Here, we present a mutational analysis of the Vbeta CDR3 of such a cross-reactive T-cell receptor (TCR), YAe62. Most YAe62 TCRs with the mutant CDR3s became less MHC promiscuous. However, others with CDR3s unrelated in sequence to the original recognized even more MHC alleles than the original TCR. Most importantly, this recognition was still dependent on the conserved CDR1/CDR2 residues. These results bolster the idea that germline TCR V elements are inherently reactive to MHC but that this reactivity is fine-tuned by the somatically generated CDR3 loops.
Rubtsova
Kira
K
Howard Hughes Medical Institute and Integrated Department of Immunology, National Jewish Health, Denver, CO 80206, USA.
Scott-Browne
James P
JP
Crawford
Frances
F
Dai
Shaodong
S
Marrack
Philippa
P
Kappler
John W
JW
D000483:Alleles; D000818:Animals; D022801:Complementarity Determining Regions; D004252:DNA Mutational Analysis; D005434:Flow Cytometry / Q000379:methods; D017353:Gene Deletion; D018095:Germ-Line Mutation; D007376:Interleukin-2 / Q000378:metabolism; D008024:Ligands; D008285:Major Histocompatibility Complex; D051379:Mice; D016688:Mice, Inbred NOD; D008968:Molecular Conformation; D010455:Peptides / Q000737:chemistry; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism*
D022801:Complementarity Determining Regions; D007376:Interleukin-2; D008024:Ligands; D010455:Peptides; D011948:Receptors, Antigen, T-Cell