Differential control of CD28-regulated in vivo immunity by the E3 ligase Cbl-b.
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.
Krawczyk
Connie M
CM
MBA, Institute of Molecular Biotechnology of the Austrian Academy of Sciences, Vienna, Austria.
Jones
Russell G
RG
Atfield
Alexandre
A
Bachmaier
Kurt
K
Arya
Sudha
S
Odermatt
Bernhard
B
Ohashi
Pamela S
PS
Penninger
Josef M
JM
D048868:Adaptor Proteins, Signal Transducing / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D000818:Animals; D000914:Antibodies, Viral / Q000096:biosynthesis; D000945:Antigens, Differentiation, T-Lymphocyte / Q000096:biosynthesis; D001327:Autoimmune Diseases / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D018106:CD28 Antigens / Q000235:genetics / Q000502:physiology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D002449:Cell Aggregation / Q000235:genetics / Q000276:immunology; D018797:Cell Cycle Proteins / Q000235:genetics / Q000502:physiology*; D016207:Cytokines / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D020566:Dendritic Cells, Follicular / Q000473:pathology; D018858:Germinal Center / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D017578:Immunoglobulin Class Switching / Q000235:genetics; D007074:Immunoglobulin G / Q000096:biosynthesis; D060889:Inducible T-Cell Co-Stimulator Protein; D051379:Mice; D018345:Mice, Knockout; D019887:Peanut Agglutinin / Q000096:biosynthesis; D010641:Phenotype; D011518:Proto-Oncogene Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D050721:Proto-Oncogene Proteins c-cbl; D051567:Proto-Oncogene Proteins c-vav; D018353:Rhabdoviridae Infections / Q000235:genetics / Q000276:immunology / Q000473:pathology; D044767:Ubiquitin-Protein Ligases / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D015854:Up-Regulation / Q000235:genetics; D014721:Vesicular stomatitis Indiana virus / Q000276:immunology
D048868:Adaptor Proteins, Signal Transducing; D000914:Antibodies, Viral; D000945:Antigens, Differentiation, T-Lymphocyte; D018106:CD28 Antigens; C118387:Cblb protein, mouse; D018797:Cell Cycle Proteins; D016207:Cytokines; C556694:Icos protein, mouse; D007074:Immunoglobulin G; D060889:Inducible T-Cell Co-Stimulator Protein; D019887:Peanut Agglutinin; D011518:Proto-Oncogene Proteins; D051567:Proto-Oncogene Proteins c-vav; C496619:Vav1 protein, mouse; D050721:Proto-Oncogene Proteins c-cbl; D044767:Ubiquitin-Protein Ligases