Aj. Sant, ISOTYPIC RESIDUES IN THE MEMBRANE PROXIMAL DOMAIN OF MHC CLASS-II BETA-CHAINS CONTROL ACTIVATION OF CD4-CELLS( T), The Journal of immunology, 150(12), 1993, pp. 5299-5310
To investigate the role that isotypic residues play during interaction
s between CD4+ T cells and MHC class II molecules, interisotypic MHC c
lass II beta-chains have been generated in which the beta1 domain is d
erived from I-A and the beta2, transmembrane, and intracytoplasmic reg
ions are derived from I-E. Interisotypic or wild-type Abeta genes have
been transfected into L cells with the genes encoding the wild-type A
alpha-chain. Transfectants bearing the recombinant beta-chain thus exp
ress an MHC class II dimer in which the amino-terminal domains that co
ntrol TCR and peptide-binding interactions are wild-type Aalpha and Ab
eta, whereas the membrane proximal domains are derived from Aalpha and
Ebeta. L cells expressing this recombinant class II molecule or wild-
type AalphaAbeta have been compared functionally for their ability to
stimulate Ag-specific T cell hybridomas and normal T cell clones and t
o activate primary alloreactive and superantigen-specific T cells. Ag-
specific T cell hybridomas vary in their ability to be activated by th
e recombinant class II molecule, and sensitivity to the isotypic form
of the membrane proximal domain correlates with expression of the CD4
molecule. CD4+ T cells distinguish between the wild-type and recombina
nt dimers, whereas CD4- T cells react equivalently with both. The reco
mbinant class II molecules are defective in activation of normal T cel
l clones and are totally deficient in activation of primary alloreacti
ve and superantigen-reactive T cells, but stimulate CD4- alloreactive
T cell hybridomas equivalently. Together, the results from these exper
iments suggest that the interisotypic dimers possess normal TCR and pe
ptide interactions, but altered CD4-dependent accessory interactions n
ecessary for activation of normal T cells. These findings indicate tha
t isotypic residues in the membrane proximal domains of MHC class II c
ontrol CD4-linked accessory function and that this accessory function
is most critical for freshly isolated CD4 lymphocytes.