Selection and function of CD4⁺ T lymphocytes in transgenic mice expressing mutant MHC class II molecules deficient in their interaction with CD4

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 α- and β-chains. We have introduced a double mutation that disrupts interaction with CD4 into the I-A(β)(k) 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 A(β)(k) mutant transgenics, peripheral CD4⁺ lymphocytes promoted B cell differentiation to plasma cells. These CD4⁺ T cells also secreted IFN-γ 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-γ and against IL-2 in the absence of these interactions. Our results have implications for the manipulation of T cell-dependent immune responses.