Effect of gene knockout on the phenotype of TNF superfamily, receptors, and receptor-associated proteins
| Gene . | Phenotype . |
|---|---|
| Cytokine | |
| TNF-β (LT-α) | Defects in secondary lymphoid organ development; disorganized splenic microarchitecture61 |
| TNF-α | No phenotypic abnormalities in LN; lack splenic primary B-cell follicles; disorganized FDC networks and germinal centers62 |
| LT-β | Defects in organogenesis of the lymphoid system; lymphocytosis in the circulation and peritoneal cavity; lymphocytic infiltrations in lungs and liver81 |
| OX40L | Defective T-cell responses82 |
| CD40L | Defective T-cell and IgG responses; hyper-IgM syndrome82 |
| FasL | Impaired activation-induced T-cell death; lymphoproliferation; autoimmunity82 |
| 4–1BBL | Defective T-cell responses82 |
| TRAIL | Delayed regression of retinal neovascularization64 |
| RANKL | Osteopetrosis; growth retardation of limbs, skull, and vertebrae; chondrodysplasia83 |
| APRIL | Normal immune system development 84 |
| Impaired IgA class switching85 | |
| BAFF | Impaired B-cell maturation86 |
| Low Ig serum levels; block in B-cell development at the T1 stage; absence of T2, mantle, and follicular zone B cells in the LN and spleen87 | |
| EDA-A1 | Ectodermal dysplasias88 * |
| EDA-A2 | Impaired development of hair, eccrine sweat glands, and teeth89 |
| Multifocal myodegeneration90 | |
| Receptor | |
| TNFR1 | Resistant to low levels of LPS; increased susceptibility to Listeria monocytogenes infection91 |
| Impaired oval cell proliferation; reduction of tumorigenesis92 | |
| TNFR2 | Increased sensitivity to bacterial pathogens; decreased sensitivity to LPS; reduced antigen-induced T-cell |
| apoptosis82 | |
| LT-βR | Absence of LN, PP; defective GC formation82 |
| OX40 | Defective T-cell responses82 |
| CD40 | Defective Ig class switching and GC formation causing immunodeficiency82 |
| Fas | Impaired activation-induced T-cell death; lymphoproliferative syndrome; autoimmunity93 |
| Accumulation of autoreactive B cells in T cell-rich zones; production of autoantibodies94 | |
| Resistant to suppression by high doses of antigen and to apoptosis in mature CD4+ T cells95 | |
| CD27 | Defective T-cell responses82 |
| CD30 | Impaired follicular GC responses; reduced recall-memory Ab responses96 |
| 4–1BB | Enhanced T-cell response but normal T-cell development97 |
| Reduced number of NK and NKT cells; resistance to LPS-induced shock syndrome98 | |
| Increased number of myeloid progenitor and mature DCs; impaired DC function99 | |
| Reduced atherosclerosis in hyperlipidemic mice100 | |
| DR5 | Normal development with an enlarged thymus66 |
| RANK | Osteopetrosis; absence of osteoclasts and LN; PP present; abnormal B-cell development82 |
| OPG | Osteoporosis; arterial calcification82 |
| FN14 | Reduced proliferative capacity; altered myotube formation101 |
| Reduced neurogenesis in the subventricular zone102 | |
| Reduced LPC numbers; attenuated inflammation; cytokine production103 | |
| TACI | Increased B-cell accumulation; splenomegaly104 |
| BAFFR | Reduced late transitional and follicular B-cell numbers; devoid of marginal zone B cells; reduced CD21 and CD23 surface expression105 |
| DR3 | Impaired negative selection and anti–CD3-induced apoptosis106 |
| GITR | Abolished anti–CD3-induced T-cell activation107 |
| EDAR | Abnormal tooth, hair, and sweat gland formation82 |
| XEDAR | No different than wild-type littermates90 |
| TROY | No apparent defects in skin appendages108 |
| DR6 | Enhanced CD4+ T-cell expansion and Th2 differentiation; enhanced splenic GC formation109 |
| Impaired JNK activity; T-cell differentiation110 | |
| CD4+ T-cell proliferation; Th differentiation111 | |
| NGFR | Decreased sensory neuron innervation; impaired heat sensitivity112 |
| Receptor-associated proteins | |
| TRAF1 | Normal lymphocyte development113 |
| Attenuation of atherosclerosis114 | |
| TRAF2 | Died prematurely; elevated sTNF levels; hypersensitivity to TNF-induced cell death115 |
| TRAF3 | Postnatal lethality; defect in T-dependent immune responses116 |
| TRAF5 | Defect in proliferation; up-regulation of surface molecules CD23, CD54, CD80, CD86, and Fas after CD40 stimulation117 |
| TRAF6 | Osteopetrosis; perinatal and postnatal lethality118 |
| Hypohidrotic ectodermal dysplasia119 | |
| TRADD | Embryonic lethal120 |
| FADD | Embryonic lethal; cardiac failure and abdominal hemorrhage121 |
| FAN | Impaired neutral sphingomyelinase activation; cutaneous barrier repair122 |
| FLICE | Perinatal lethal123 |
| RIP | Perinatal lethal124 |
| IKK-α | Abnormal morphogenesis (limb and skeletal patterning; proliferation and differentiation of epidermal keratinocytes)125 |
| IKK-β | Died at mid-gestation126 |
| Apaf-1 | Reduced apoptosis in the brain; hyperproliferation of neuronal cells127 |
| Caspase-9 | Embryonic lethal; defect in brain development128 |
| Caspase-3 | Decreased apoptosis in the brain; premature lethality129 |
| EDARADD | Hypohidrotic ectodermal dysplasia130 |
| Act1 | B cell–mediated autoimmune phenotypes131 |
| Gene . | Phenotype . |
|---|---|
| Cytokine | |
| TNF-β (LT-α) | Defects in secondary lymphoid organ development; disorganized splenic microarchitecture61 |
| TNF-α | No phenotypic abnormalities in LN; lack splenic primary B-cell follicles; disorganized FDC networks and germinal centers62 |
| LT-β | Defects in organogenesis of the lymphoid system; lymphocytosis in the circulation and peritoneal cavity; lymphocytic infiltrations in lungs and liver81 |
| OX40L | Defective T-cell responses82 |
| CD40L | Defective T-cell and IgG responses; hyper-IgM syndrome82 |
| FasL | Impaired activation-induced T-cell death; lymphoproliferation; autoimmunity82 |
| 4–1BBL | Defective T-cell responses82 |
| TRAIL | Delayed regression of retinal neovascularization64 |
| RANKL | Osteopetrosis; growth retardation of limbs, skull, and vertebrae; chondrodysplasia83 |
| APRIL | Normal immune system development 84 |
| Impaired IgA class switching85 | |
| BAFF | Impaired B-cell maturation86 |
| Low Ig serum levels; block in B-cell development at the T1 stage; absence of T2, mantle, and follicular zone B cells in the LN and spleen87 | |
| EDA-A1 | Ectodermal dysplasias88 * |
| EDA-A2 | Impaired development of hair, eccrine sweat glands, and teeth89 |
| Multifocal myodegeneration90 | |
| Receptor | |
| TNFR1 | Resistant to low levels of LPS; increased susceptibility to Listeria monocytogenes infection91 |
| Impaired oval cell proliferation; reduction of tumorigenesis92 | |
| TNFR2 | Increased sensitivity to bacterial pathogens; decreased sensitivity to LPS; reduced antigen-induced T-cell |
| apoptosis82 | |
| LT-βR | Absence of LN, PP; defective GC formation82 |
| OX40 | Defective T-cell responses82 |
| CD40 | Defective Ig class switching and GC formation causing immunodeficiency82 |
| Fas | Impaired activation-induced T-cell death; lymphoproliferative syndrome; autoimmunity93 |
| Accumulation of autoreactive B cells in T cell-rich zones; production of autoantibodies94 | |
| Resistant to suppression by high doses of antigen and to apoptosis in mature CD4+ T cells95 | |
| CD27 | Defective T-cell responses82 |
| CD30 | Impaired follicular GC responses; reduced recall-memory Ab responses96 |
| 4–1BB | Enhanced T-cell response but normal T-cell development97 |
| Reduced number of NK and NKT cells; resistance to LPS-induced shock syndrome98 | |
| Increased number of myeloid progenitor and mature DCs; impaired DC function99 | |
| Reduced atherosclerosis in hyperlipidemic mice100 | |
| DR5 | Normal development with an enlarged thymus66 |
| RANK | Osteopetrosis; absence of osteoclasts and LN; PP present; abnormal B-cell development82 |
| OPG | Osteoporosis; arterial calcification82 |
| FN14 | Reduced proliferative capacity; altered myotube formation101 |
| Reduced neurogenesis in the subventricular zone102 | |
| Reduced LPC numbers; attenuated inflammation; cytokine production103 | |
| TACI | Increased B-cell accumulation; splenomegaly104 |
| BAFFR | Reduced late transitional and follicular B-cell numbers; devoid of marginal zone B cells; reduced CD21 and CD23 surface expression105 |
| DR3 | Impaired negative selection and anti–CD3-induced apoptosis106 |
| GITR | Abolished anti–CD3-induced T-cell activation107 |
| EDAR | Abnormal tooth, hair, and sweat gland formation82 |
| XEDAR | No different than wild-type littermates90 |
| TROY | No apparent defects in skin appendages108 |
| DR6 | Enhanced CD4+ T-cell expansion and Th2 differentiation; enhanced splenic GC formation109 |
| Impaired JNK activity; T-cell differentiation110 | |
| CD4+ T-cell proliferation; Th differentiation111 | |
| NGFR | Decreased sensory neuron innervation; impaired heat sensitivity112 |
| Receptor-associated proteins | |
| TRAF1 | Normal lymphocyte development113 |
| Attenuation of atherosclerosis114 | |
| TRAF2 | Died prematurely; elevated sTNF levels; hypersensitivity to TNF-induced cell death115 |
| TRAF3 | Postnatal lethality; defect in T-dependent immune responses116 |
| TRAF5 | Defect in proliferation; up-regulation of surface molecules CD23, CD54, CD80, CD86, and Fas after CD40 stimulation117 |
| TRAF6 | Osteopetrosis; perinatal and postnatal lethality118 |
| Hypohidrotic ectodermal dysplasia119 | |
| TRADD | Embryonic lethal120 |
| FADD | Embryonic lethal; cardiac failure and abdominal hemorrhage121 |
| FAN | Impaired neutral sphingomyelinase activation; cutaneous barrier repair122 |
| FLICE | Perinatal lethal123 |
| RIP | Perinatal lethal124 |
| IKK-α | Abnormal morphogenesis (limb and skeletal patterning; proliferation and differentiation of epidermal keratinocytes)125 |
| IKK-β | Died at mid-gestation126 |
| Apaf-1 | Reduced apoptosis in the brain; hyperproliferation of neuronal cells127 |
| Caspase-9 | Embryonic lethal; defect in brain development128 |
| Caspase-3 | Decreased apoptosis in the brain; premature lethality129 |
| EDARADD | Hypohidrotic ectodermal dysplasia130 |
| Act1 | B cell–mediated autoimmune phenotypes131 |
Fas indicates fibroblast-associated; FN14, fibroblast growth factor-inducible immediate-early response gene 14; GITR, glucocorticoid-induced TND receptor; EDAR, EDA receptor; XEDAR, X-linked ectodysplasin receptor; TROY, TNFRSF expressed on the mouse embryo; NGFR, nerve growth factor receptor; FAN, factor associated with neutral SMase activation; FLICE, FADD-like IL-1β-converting enzyme; Apaf-1, apoptotic protease activating factor-1; EDARADD, ectodysplasin-A receptor-associated adapter protein; LN, lymph node; FDC, follicular dendritic cell; LPS, lipopolysaccharide; PP, Peyer patches; GC, germinal center; and sTNF, serum TNF.
Study performed in human, others in mouse model.