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Department of Immunology, Division of Medicine, Imperial College of Science, Technology, and Medicine, Hammersmith Hospital, Du Cane Road, London, United Kingdom
Activation of T lymphocytes is dependent on multiple
ligand-receptor interactions. The possibility that TCR dimerization
contributes to T cell triggering was raised by the crystallographic
analysis of MHC class II molecules. The MHC class II molecules
associated as double dimers, and in such a way that two TCR (and two
CD4 molecules) could bind simultaneously. Several subsequent studies
have lent support to this concept, although the role of TCR
cross-linking in T cell activation remains unclear. Using DRA cDNAs
modified to encode two different C-terminal tags, no evidence of
constitutive double dimer formation was obtained following
immunoprecipitation and Western blotting from cells transiently
transfected with wild-type DRB and tagged DRA constructs, together with
invariant chain and HLA-DM. To determine whether MHC class II molecules
contribute actively to TCR-dependent dimerization and consequent T cell
activation, panels of HLA-DR1
and H2-Ek cDNAs were
generated with mutations in the sequences encoding the interface
regions of the MHC class II double dimer. Stable DAP.3 transfectants
expressing these cDNAs were generated and characterized biochemically
and functionally. Substitutions in either interface region I or III did
not affect T cell activation, whereas combinations of amino acid
substitutions in both regions led to substantial inhibition of
proliferation or IL-2 secretion by human and murine T cells. Because
the amino acid-substituted molecules were serologically
indistinguishable from wild type, bound antigenic peptide with equal
efficiency, and induced Ag-dependent CD25 expression indicating TCR
recognition, the reduced ability of the mutants to induce full T cell
activation is most likely the result of impaired double dimer
formation. These data suggest that MHC class II molecules, due to their
structural properties, actively contribute to TCR
cross-linking.
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