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 alpha- and beta-chains. We have introduced a double mutation 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 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(beta)k mutant transgenics, peripheral CD4+ lymphocytes promoted B cell differentiation to plasma cells. These CD4+ T cells also secreted IFN-gamma 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-gamma and against IL-2 in the absence of these interactions. Our results have implications for the manipulation of T cell-dependent immune responses.
Gilfillan
S
S
Institut de Genetique et de Biologie Moleculaire et Cellulaire, Illkirch, C.U. de Strasbourg, France.
Shen
X
X
König
R
R
D019943:Amino Acid Substitution; D000818:Animals; D000917:Antibody Formation; D000942:Antigens, Bacterial / Q000276:immunology; D001665:Binding Sites; D015704:CD4 Antigens / Q000276:immunology / Q000378:metabolism*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D016827:CD8 Antigens / Q000276:immunology; D002454:Cell Differentiation; D002478:Cells, Cultured; D017637:Clonal Deletion; D004768:Enterotoxins / Q000276:immunology; D006433:Hemocyanins / Q000276:immunology; D000949:Histocompatibility Antigens Class II / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D007114:Immunization; D007156:Immunologic Memory; D008198:Lymph Nodes / Q000166:cytology; D051379:Mice; D008822:Mice, Transgenic; D016296:Mutagenesis; D013154:Spleen / Q000166:cytology; D013329:Structure-Activity Relationship; D018089:Superantigens / Q000276:immunology
D000942:Antigens, Bacterial; D015704:CD4 Antigens; D016827:CD8 Antigens; D004768:Enterotoxins; D000949:Histocompatibility Antigens Class II; D018089:Superantigens; C026066:enterotoxin A, Staphylococcal; D006433:Hemocyanins; C032808:keyhole-limpet hemocyanin