Abstract
The E3 ubiquitin ligase Casitas B cell lymphoma-b (Cbl-b) plays a critical role in the development of autoimmunity and sets the threshold for T cell activation. In the absence of Cbl-b, T cells stimulated via the TCR respond similarly to those that have received a CD28-mediated costimulatory signal, suggesting that the absence of Cbl-b substitutes for CD28-mediated costimulation. In this study, we show that loss of Cbl-b restores Ig class switching and germinal center formation in Vav1 mutant mice in response to an in vivo viral challenge. Genetic inactivation of Cbl-b also rescues impaired antiviral IgG production in CD28-mutant mice. Moreover, loss of CD28 results in disorganization of follicular dendritic cell clusters, which is also rescued by the Cbl-b mutation. Intriguingly, despite restored antiviral in vivo immunity and follicular dendritic cell clusters, loss of Cbl-b did not rescue germinal center formation in CD28-deficient mice. Mechanistically, in vivo vesicular stomatitis virus-induced IL-4 and IFN-gamma production and up-regulation of the inducible costimulatory molecule ICOS were dependent on CD28, and could not be rescued by the loss of Cbl-b. These data provide genetic evidence that CD28-dependent in vivo immune responses and Ig class switching can be genetically uncoupled from germinal center formation and ICOS induction by Cbl-b-Vav1-regulated signaling pathways.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing / deficiency
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Adaptor Proteins, Signal Transducing / genetics
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Adaptor Proteins, Signal Transducing / physiology*
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Animals
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Antibodies, Viral / biosynthesis
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Antigens, Differentiation, T-Lymphocyte / biosynthesis
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Autoimmune Diseases / genetics
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Autoimmune Diseases / immunology*
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Autoimmune Diseases / pathology
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CD28 Antigens / genetics
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CD28 Antigens / physiology*
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CD4-Positive T-Lymphocytes / immunology
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CD4-Positive T-Lymphocytes / metabolism
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CD4-Positive T-Lymphocytes / pathology
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Cell Aggregation / genetics
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Cell Aggregation / immunology
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Cell Cycle Proteins / genetics
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Cell Cycle Proteins / physiology*
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Cytokines / antagonists & inhibitors
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Cytokines / biosynthesis
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Dendritic Cells, Follicular / pathology
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Germinal Center / immunology
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Germinal Center / metabolism
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Germinal Center / pathology
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Immunoglobulin Class Switching / genetics
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Immunoglobulin G / biosynthesis
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Inducible T-Cell Co-Stimulator Protein
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Mice
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Mice, Knockout
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Peanut Agglutinin / biosynthesis
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Phenotype
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Proto-Oncogene Proteins / deficiency
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins / physiology*
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Proto-Oncogene Proteins c-cbl
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Proto-Oncogene Proteins c-vav
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Rhabdoviridae Infections / genetics
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Rhabdoviridae Infections / immunology
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Rhabdoviridae Infections / pathology
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Ubiquitin-Protein Ligases / deficiency
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Ubiquitin-Protein Ligases / genetics
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Ubiquitin-Protein Ligases / physiology*
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Up-Regulation / genetics
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Vesicular stomatitis Indiana virus / immunology
Substances
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Adaptor Proteins, Signal Transducing
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Antibodies, Viral
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Antigens, Differentiation, T-Lymphocyte
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CD28 Antigens
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Cblb protein, mouse
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Cell Cycle Proteins
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Cytokines
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Icos protein, mouse
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Immunoglobulin G
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Inducible T-Cell Co-Stimulator Protein
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Peanut Agglutinin
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Proto-Oncogene Proteins
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Proto-Oncogene Proteins c-vav
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Vav1 protein, mouse
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Proto-Oncogene Proteins c-cbl
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Ubiquitin-Protein Ligases