Journal of Experimental Medicine, Vol 179, 1637-1643, Copyright © 1994 by Rockefeller University Press
Holes in the T cell repertoire to myelin basic protein owing to the absence of the D beta 2-J beta 2 gene cluster: implications for T cell receptor recognition and autoimmunity
V Kumar and E Sercarz
Department of Microbiology and Molecular Genetics, University of California, Los Angeles 90024-1489.
Models of T cell recognition suggest that amino acid residues in the CDR3
region of the T cell receptor (TCR) alpha or beta chain directly contact
the major histocompatibility complex-bound peptide, and thus are crucial
for providing peptide specificity. T cells derived from B10.PL or PL/J mice
of H-2u haplotype, use only D beta 2 and J beta 2 gene segments in the
recognition of the dominant determinant, Ac1-9/Au, of myelin basic protein
(MBP). New Zealand White (NZW) mice, with identical class II H-2u genes
(I-A and I-E), carry an 8.8-kb deletion in their TCR beta chain locus
encompassing D beta 2 and J beta 2 gene segments. How does this deletion of
the crucial D beta 2-J beta 2 region in NZW mice influence specific
responses to Ac1-9/Au as well as to other known Au or Eu determinants of
MBP? We found that these mice respond very poorly to the dominant Ac1-9/Au
and to the subdominant 31- 50/Eu determinant in in vitro proliferation
assays as well as in their in vivo capacity to induce experimental
autoimmune encephalomyelitis. This loss of response is apparently owing to
the absence of high avidity TCRs with essential CDR3 residues contributed
by D beta 2 or J beta 2 gene segments. These data reveal constraints in the
recognition of certain antigenic structures, and further support a
TCR-recognition model in which CDR3 residues of the TCR alpha and beta
chains constitute the antigenic peptide-binding sites on the TCR molecule.
Implications for autoimmune manifestations contributed by NZW genes in (NZB
x NZW)F1 disease are also discussed.
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