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J. Exp. Med.,
Volume 189, Number 3, February 1, 1999 509-520
Domain
By
From the Center for Immunology and Department of Microbiology, University of Texas Southwestern
Medical Center at Dallas, Dallas, Texas 75235-8576
The role of two central residues (K68, E69) of the fourth hypervariable loop of the V
domain
(HV4) in antigen recognition by an MHC class II-restricted T cell receptor (TCR) has been
analyzed. The TCR recognizes the NH2-terminal peptide of myelin basic protein (Ac1-11,
acetylated at NH2 terminus) associated with the class II MHC molecule I-Au. Lysine 68 (K68)
and glutamic acid 69 (E69) of HV4 have been mutated both individually and simultaneously
to alanine (K68A, E69A). The responsiveness of transfectants bearing wild-type and mutated
TCRs to Ac1-11-I-Au complexes has been analyzed in the presence and absence of expression of the coreceptor CD4. The data demonstrate that in the absence of CD4 expression, K68
plays a central role in antigen responsiveness. In contrast, the effect of mutating E69 to alanine
is less marked. CD4 coexpression can partially compensate for the loss of activity of the K68A
mutant transfectants, resulting in responses that, relative to those of the wild-type transfectants,
are highly sensitive to anti-CD4 antibody blockade. The observations support models of T cell
activation in which both the affinity of the TCR for cognate ligand and the involvement of
coreceptors determine the outcome of the T cell-antigen-presenting cell interaction.
domain;
fourth hypervariable loop;
antigen recognition;
CD4 coreceptor
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