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Table 6 In vivo functions of TRAFs in mice

From: TRAF molecules in cell signaling and in human diseases

Genotype Type of knockout Phenotype References
TRAF1
TRAF1−/− Germline Viable and normal lymphocyte development [173]
   Skin hypersensitive to TNF-induced necrosis [173]
   Hyperproliferation in response to T cell receptor signaling [173]
   Enhanced Th2 responses [266]
   Lack of 4-1BB-mediated survival responses in CD8 and memory T cells [78, 79, 171]
   Required for 4-1BB-induced NF-κB1 activation in T cells [31]
   Constitutive NF-κB2 activation in CD8 T cells [31]
TRAF2    
TRAF2−/− Germline Progressively runted and die within 3 weeks after birth [267]
   Atrophy of the thymus and spleen; depletion of B cell precursors [267]
   Elevated serum TNF levels; cells sensitive to TNF-induced apoptosis [267]
   Severe reduction in TNF-mediated JNK activation [267]
   Severe colitis; drastic changes in the colonic microbiota [261]
   Increased number of Th17 cells in the colonic lamina propria [261]
   Apoptosis of colonic epithelial cells due to TNFR1 signaling [261]
   IL-10-secreting neutrophils accumulated in peripheral blood and bone marrow [262]
TRAF2flox/flox, CD19-Cre B cell-specific Prolonged B cell survival independent of BAFF [36]
   Splenomegaly and lymphadenopathy [36]
   Constitutive NF-κB2 activation in B cells [36]
   Slower and decreased CD40-induced phosphorylation of JNK, p38 and ERK [74]
   Reduced germinal center formation following SRBC immunization [74]
TRAF2flox/flox, Lck-Cre T cell-specific Normal T cell survival; constitutive NF-κB2 activation in T cells [36]
TRAF2flox/flox, Albumin-Cre Hepatocyte-specific Severely impaired hyperglycemic response to glucagon [268]
TRAF3    
TRAF3−/− Germline Progressively runted; die by 10 days after birth [269]
   Impaired T cell responses [269]
TRAF3flox/flox, CD19-Cre B cell-specific Prolonged B cell survival independent of BAFF [36, 270]
   Splenomegaly and lymphadenopathy [36, 270]
   Autoimmune manifestations and hyperimmunoglobulinemia [270]
   Increased T-independent antibody responses [270]
   Development of B1 lymphomas and splenic marginal zone lymphomas [271]
   Enhanced signaling by TLR3, TLR4, TLR7, and TLR9 in B cells [272]
   Accelerated CD40-induced phosphorylation of JNK, p38 and ERK [74]
TRAF3flox/flox, Lck-Cre T cell-specific Normal T cell survival; constitutive NF-kB2 activation in T cells [36]
TRAF3flox/flox, CD4-Cre T cell-specific Normal T cell survival; constitutive NF-kB2 activation in T cells [11]
   Normal CD4 and CD8 T cell development; increased number of Treg cells [11]
   Defective T-dependent antibody responses [11]
   Impaired T cell-mediated immunity to bacterial infection [11]
   Defective T cell responses to co-stimulation by T cell receptor and CD28 [11]
TRAF4    
TRAF4−/− Germline Embryonic lethal but with great individual variation [258, 259]
   Respiratory disorder and wheezing caused by tracheal ring disruption [258, 259]
   Surviving mutant mice manifest numerous developmental abnormalities [258, 259]
   Altered locomotion coordination typical of ataxia [258, 259]
   High incidence of spina bifida [258, 259]
   Degeneration of a high number of Purkinje cells [260]
   Increased rates of pulmonary inflammation [260]
   Reduced migration of DCs; normal development of T and B lymphocytes [273]
   Inhibits IL-17 signaling and Th17-mediated autoimmune encephalomyelitis [164]
TRAF5    
TRAF5−/− Germline Viable and normal development [274]
   Mild defect in T-dependent antibody responses [274]
   Defective in Th1/Th2 differentiation [275]
TRAF6    
TRAF6−/− Germline Perinatal and postnatal lethality [264, 265]
   Severe osteopetrosis; defective in osteoclast formation [264, 265]
   Defective IL-1, CD40 and LPS signaling in lymphocytes [264, 265]
   Defective in lymph node organogenesis [265]
   Reduced number of immature B cells in the bone marrow [265]
   Severe defect in the Treg development in thymus [276]
   Defective development, maturation and activation of DCs [277]
   Impaired cytokine production in mast cells following FcεRI aggregation [278]
   Hypohidrotic ectodermal dysplasia [279]
TRAF6flox/flox, CD19-Cre B cell-specific Reduced number of mature B cells in the bone marrow and spleen [280]
   Impaired T-dependent and T-independent antibody responses [280]
   Lack of CD5+ B-1 cells [280]
TRAF6flox/flox, CD4-Cre T cell-specific Multiorgan inflammatory disease; hyperactivation of the PI3K-Akt pathway [281]
   Resistant to suppression by CD4+CD25+ regulatory T cells [281]
   Resistant to anergizing signals [282]
   A profound defect in generating CD8 memory T cells; [283]
   Defective AMPK activation and mitochondrial fatty acid oxidation [283]
   Specific increase in Th17 differentiation [284]
   More sensitive to TGFβ-induced Smad2/3 activation and proliferation arrest [284]
   A severe defect in the Treg development [276]
TRAF6flox/flox, MCK-Cre Skeletal muscle-specific Improved muscle preservation in response to starvation or cancer cachexia [60, 285, 286]
   Improved regeneration of myofibers upon injury [60, 285, 286]
   Augmented the M2 macrophage phenotype in injured muscle tissues [60, 285, 286]
   Upregulated Notch signaling and reduced inflammatory cytokine production [287, 288]