ABSTRACT
The influence of costimulation on the activation of naive CD8+ T cells and thymocytes was studied in vitro using H-Y-specific TCR-transgenic mice and H-Y antigenic peptide. Using a variety of physiological APC types, the activation of naive CD8+ T cells depended strictly on costimulation, which could not be substituted by high epitope density. T cell activation is known to be regulated by the interactions between CD86/CD80 and CD28/CD152, although it remains unclear whether the B7 isoforms have distinct roles. Addition of soluble anti-CD86 Ab led to profound inhibition of T cell reactivity, further confirming the importance of costimulation in naive CD8+ T cell activation. Finally, TCR engagement in the absence of costimulation had no effect on the subsequent reactivity of peripheral naive transgenic CD8+ T cells, but induced nonresponsiveness in mature CD8+ transgenic thymocytes. Collectively, these results demonstrate the importance of costimulation for naive CD8+ T cell activation, suggest that CD80 and CD86 can mediate opposing effects, possibly due to differential interaction with CD152 and CD28, and indicate differences in the sensitivity of immature vs mature CD8+ T cells to the induction of nonresponsiveness following costimulation-deficient Ag presentation.
Subject(s)
CD8-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/metabolism , Epitopes, T-Lymphocyte/genetics , Immunoconjugates , Lymphocyte Activation/genetics , Receptors, Antigen, T-Cell, alpha-beta/genetics , Abatacept , Adjuvants, Immunologic/pharmacology , Adjuvants, Immunologic/physiology , Animals , Antibodies, Monoclonal/pharmacology , Antigen Presentation/genetics , Antigen-Presenting Cells/immunology , Antigen-Presenting Cells/metabolism , Antigens, CD/metabolism , Antigens, CD/physiology , Antigens, Differentiation/pharmacology , B7-1 Antigen/metabolism , B7-1 Antigen/physiology , B7-2 Antigen , CD28 Antigens/immunology , CD28 Antigens/pharmacology , CTLA-4 Antigen , Cells, Cultured , Clonal Anergy/genetics , Clonal Anergy/immunology , H-Y Antigen/immunology , Immunoglobulin Fab Fragments/pharmacology , Immunophenotyping , Immunosuppressive Agents/pharmacology , Interleukin-2/pharmacology , Lymphocyte Activation/immunology , Membrane Glycoproteins/metabolism , Membrane Glycoproteins/physiology , Mice , Mice, Inbred C57BL , Mice, Inbred CBA , Mice, Transgenic , SolubilitySubject(s)
B-Lymphocytes/drug effects , Hemagglutinins/pharmacology , Lymphocyte Activation/drug effects , Apoptosis/drug effects , B-Lymphocytes/cytology , B-Lymphocytes/immunology , Burkitt Lymphoma , Cell Division/drug effects , Cell Line , Cell Survival/drug effects , Galactosides , Galectins , Humans , Palatine Tonsil , Tumor Cells, CulturedABSTRACT
B lymphocytes are activated following antigen stimulation of the B cell receptor but require co-stimulation with accessory molecules provided by interleukin (IL)-4/CD40 ligand for cell cycle progression and proliferation. By analyzing a panel of 11 early response genes induced by cross-linking of surface immunoglobulin, we show that CD40 signaling alone induces only 2 genes, c-myc together with an anonymous gene, 3L3, and that these are distinct from the set of genes induced in response to IL-4. Co-stimulation with the proliferative combination of anti-mu, IL-4 + CD40 signaling led to a fourfold enhancement of egr-2/krox 20 expression over that seen with anti-mu alone. Egr-2 expression/activity was selectively inhibited by the immunosuppressive drug cyclosporin A, and antisense oligonucleotide blockade of Egr-2 activity elicited a dose-dependent inhibition of B cell proliferation. Taken together, these observations show that the early gene regulatory programs coupled to different surface receptors on B cells are largely distinct from each other, but that certain genes, exemplified by egr-2, may represent a point of convergence in the integration of different signaling pathways into the B cell proliferative response.
