ABSTRACT
To study the role of the direct and indirect pathways in achieving tolerance, we used genetically altered mouse strains in two ways: 1) MHC class II-deficient mice were used as donors of skin and cardiac grafts to eliminate the direct CD4(+) T cell response, and 2) B6 II(-)4(+) mice, which are MHC class II-deficient mice expressing an MHC class II transgene only on thymic epithelium, were used as recipients of normal grafts. These mice cannot mount an indirect response. Eliminating the indirect pathway actually made it more difficult to achieve prolonged allograft survival when we used costimulatory blockade than when both pathways were available. Costimulatory blockade was ineffective even when CD4(+) T cells from normal animals were transferred into recipients that lacked MHC class II molecules. These results suggest that an active CD4(+) response through the indirect pathway is necessary for costimulatory blockade to be effective in prolonging allograft survival.
Subject(s)
Graft Enhancement, Immunologic , Graft Survival , Heart Transplantation/immunology , Histocompatibility Antigens Class II/metabolism , Immunoconjugates , Transplantation Tolerance , Abatacept , Adoptive Transfer , Animals , Antibodies/immunology , Antigens, CD , Antigens, Differentiation/immunology , CD4-Positive T-Lymphocytes/immunology , CD4-Positive T-Lymphocytes/transplantation , CD40 Ligand/immunology , CTLA-4 Antigen , Cells, Cultured , Histocompatibility Antigens Class II/genetics , Mice , Mice, Knockout , Skin Transplantation/immunologyABSTRACT
NFAT transcription factors play critical roles in gene transcription during immune responses. To investigate further the two most prominent NFAT family members, NFATc1 and NFATc2, we generated mice bearing lymphoid systems devoid of both. Doubly deficient T cells displayed cell surface markers of activation yet were significantly deficient in the development of multiple effector functions, including Th cytokine production, surface effector molecule expression, and cytolytic activity. Nevertheless, doubly deficient B cells were hyperactivated, as evidenced by extremely elevated serum IgG1 and IgE, as well as plasma cell expansion and infiltration of end organs. Thus, in T cells, NFATc1 and NFATc2 are dispensable for inflammatory reactivity but are required for effector differentiation, while in B cells, NFATs regulate both normal homeostasis and differentiation.
Subject(s)
B-Lymphocytes/immunology , DNA-Binding Proteins/immunology , Lymphocyte Activation/immunology , Nuclear Proteins , T-Lymphocytes/immunology , Transcription Factors/immunology , Animals , B-Lymphocytes/cytology , Cell Differentiation , Cytokines/biosynthesis , Lymphoid Tissue , Mice , Mice, Inbred BALB C , Mice, Knockout , NFATC Transcription Factors , T-Lymphocytes/cytologyABSTRACT
The critical function of NFAT proteins in maintaining lymphoid homeostasis was revealed in mice lacking both NFATp and NFAT4 (DKO). DKO mice exhibit increased lymphoproliferation, decreased activation-induced cell death, and impaired induction of FasL. The transcription factors Egr2 and Egr3 are potent activators of FasL expression. Here we find that Egr2 and Egr3 are NFAT target genes. Activation of FasL occurs via the NFAT-dependent induction of Egr3, as demonstrated by the ability of exogenously provided NFATp to restore Egr-dependent FasL promoter activity in DKO lymph node cells. Further, Egr3 expression is enriched in Th1 cells, suggesting a molecular basis for the known preferential expression of FasL in the Th1 versus Th2 subset.
