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,
*
Institut de Genetique et de Biologie Moleculaire et Cellulaire, Illkirch, C.U. de Strasbourg, France;
Department of Microbiology and Immunology and
Sealy Center for Molecular Science, University of Texas Medical Branch, Galveston, TX 77555
Interactions of the T cell coreceptors, CD4 and CD8, with MHC
molecules participate in regulating thymocyte development and T
lymphocyte activation and differentiation to memory T cells. However,
the exact roles of these interactions in normal T cell development and
function remain unclear. CD4 interacts with class II MHC7 molecules via
several noncontiguous regions in both the class II MHC 
- and
ß-chains. We have introduced a double mutation that disrupts
interaction with CD4 into the I-Aßk gene and
used this construct to generate transgenic mice expressing only mutant
class II MHC. Although CD4+ thymocytes matured to the
single-positive stage in these mice, their frequency was reduced by
threefold compared with that of wild-type transgenics. Positive
selection of CD4+ T cells in the mutant transgenic mice may
have been mediated by TCRs with a higher than usual affinity for class
II MHC/Ag complexes. In Aßk mutant
transgenics, peripheral CD4+ lymphocytes promoted B cell
differentiation to plasma cells. These CD4+ T cells also
secreted IFN-
in response to various stimuli (e.g., protein Ag,
bacterial superantigen, and alloantigen), but were deficient in IL-2
secretion. Interactions between CD4 and class II MHC molecules appeared
to regulate lymphokine production, with a strong bias toward IFN-
and against IL-2 in the absence of these interactions. Our results have
implications for the manipulation of T cell-dependent immune
responses.
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