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 par ticipate in regulating thymocyte development and T lymphocyte activation an d differentiation to memory T cells. However, the exact roles of these inte ractions in normal T cell development and function remain unclear. CD4 inte racts with class II MHC7 molecules via several noncontiguous regions in bot h the class II MHC alpha- and beta-chains, We have introduced a double muta tion that disrupts interaction with CD4 into the I-A(beta)(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 th ese mice, their frequency was reduced by threefold compared with that of wi ld-type transgenics, Positive selection of CD4(+) T cells in the mutant tra nsgenic mice may have been mediated by TCRs with a higher than usual affini ty for class II MHC/Ag complexes. In A(beta)(k) mutant transgenics, periphe ral CD4(+) lymphocytes promoted B cell differentiation to plasma cells. The se CD4(+) T cells also secreted IFN-gamma in response to various stimuli (e .g., protein Ag, bacterial superantigen, and alloantigen), but were deficie nt in IL-2 secretion. Interactions between CD4 and class II MHC molecules a ppeared to regulate lymphokine production, with a strong bias toward IFN-ga mma and against IL-2 in the absence of these interactions. Our results have implications for the manipulation of T cell-dependent immune responses.