Mouse Genome Informatics
hm1
    Tbx21tm1Glm/Tbx21tm1Glm
B6.129S6-Tbx21tm1Glm
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
immune system
• wild-type CD4+ T cells polarized under Th17 conditions can be converted to a Th1-like cells (i.e. they express IFN-gamma) by culturing with IL-12
• mutant polarized Th17 CD4+ T cells fail to convert to the Th1-like state in the presence of IL-12

hematopoietic system
• wild-type CD4+ T cells polarized under Th17 conditions can be converted to a Th1-like cells (i.e. they express IFN-gamma) by culturing with IL-12
• mutant polarized Th17 CD4+ T cells fail to convert to the Th1-like state in the presence of IL-12


Mouse Genome Informatics
hm2
    Tbx21tm1Glm/Tbx21tm1Glm
C.129S6-Tbx21tm1Glm/J
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
immune system
• primed splenocytes from deficient animals produce less interferon-gamma (Ifng) than wild-type cells, but produce much increased levels of Il-10 throughout the course of the disease compared to wild-type
• however, recall responses of in vivo primed splenocytes from mutants 10 days after immunization are comparable to wild-type as significant proliferation in response to PLP peptide is observed ex vivo
• wild-type mice show presence of Ifng in the spinal cord after disease development, while mutants show no Ifng but significant 1l-10 production
• when immunized with PLP (proteolipid protein) peptide 180-199, mutants are resistant to development of clinical experimental autoimmune encephalitis (EAE) disease while wild-type littermates develop a more severe form of disease
• Tbx21-deficient mice show a lower incidence of EAE over a period of 40 days vs wild-type controls
• mutants have a very mild clinical course of disease whereas wild-type show an earlier onset and develop a higher disease grade (2.5 vs 1.25)
• upon adoptive transfer of wild-type PLP-specific T cells, mutants show decreased EAE severity compared to wild-type
• CNS of mutants show less infiltration of leukocytes into the spinal cord at 5 days after EAE onset (15 days); very little CD4+ T cell infiltration is seen compared to wild-type spinal cords

nervous system
• CNS of mutants show less infiltration of leukocytes into the spinal cord at 5 days after EAE onset (15 days); very little CD4+ T cell infiltration is seen compared to wild-type spinal cords

hematopoietic system
• primed splenocytes from deficient animals produce less interferon-gamma (Ifng) than wild-type cells, but produce much increased levels of Il-10 throughout the course of the disease compared to wild-type
• however, recall responses of in vivo primed splenocytes from mutants 10 days after immunization are comparable to wild-type as significant proliferation in response to PLP peptide is observed ex vivo


Mouse Genome Informatics
hm3
    Tbx21tm1Glm/Tbx21tm1Glm
involves: 129S6/SvEvTac
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
immune system
• Th1 and Tc1 show a modest decrease in migration to CXCL10
• DSS-treated mice develop more extensive and severe inflammatory infiltrate, edema, extensive ulceration, and crypt loss compared with similarly treated wild-type mice
• T cells from mice immunized with myelin oligodendrocyte glycoprotein (MOG) peptide show more interferon gamma (Ifng) and Ifng-secreting cells than wild-type ; numbers of IL-17a producing cells as well as IL-17a levels are higher than in wild-type
• when CD8+ T cells are cultured in Th17-polarizing conditions 2-3 fold more IL17 producing cells are produced

homeostasis/metabolism
• T cells from mice immunized with myelin oligodendrocyte glycoprotein (MOG) peptide show more interferon gamma (Ifng) and Ifng-secreting cells than wild-type ; numbers of IL-17a producing cells as well as IL-17a levels are higher than in wild-type

digestive/alimentary system
• DSS-treated mice develop more extensive and severe inflammatory infiltrate, edema, extensive ulceration, and crypt loss compared with similarly treated wild-type mice

hematopoietic system
• Th1 and Tc1 show a modest decrease in migration to CXCL10

cellular
• Th1 and Tc1 show a modest decrease in migration to CXCL10


Mouse Genome Informatics
hm4
    Tbx21tm1Glm/Tbx21tm1Glm
involves: 129S6/SvEvTac * C57BL/6
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
hematopoietic system
• number of Ifng producing cells (Th1) decreases while Th2 cells producing Il-4 and Il-5 increase in number
• number of Ifng producing cells (Th1) decreases while Th2 cells producing Il-4 and Il-5 increase in number
• differentiation of CD4 T cells into helper T cell subsets is impaired or altered; cells fail to differentiate into Th1 lineage and default to Th2 fate
• mutants have normal numbers of Ifng-producing CD8 T cells; as well, unexpectedly, mutant CD8 T cells produce equivalent levels of Ifng to wild-type
• normal mixed response to protein antigen immunization is altered; after TNP-KLH treatment mice produced decreased IgG2a and very slightly increased IgG1 compared to controls at day 12
• splenic NK cells from mutants produce less Ifng in response to Il-12 or Il-18 than NK cells from wild-type
• NK cells from mutants are impaired in ability to lyse YAC-1 cells compared to wild-type
• NK cells from mutants treated with poly(I:C) for activation lyse tumor cell targets equivalently to wild-type NK cells

immune system
• number of Ifng producing cells (Th1) decreases while Th2 cells producing Il-4 and Il-5 increase in number
• number of Ifng producing cells (Th1) decreases while Th2 cells producing Il-4 and Il-5 increase in number
• differentiation of CD4 T cells into helper T cell subsets is impaired or altered; cells fail to differentiate into Th1 lineage and default to Th2 fate
• mutants have normal numbers of Ifng-producing CD8 T cells; as well, unexpectedly, mutant CD8 T cells produce equivalent levels of Ifng to wild-type
• normal mixed response to protein antigen immunization is altered; after TNP-KLH treatment mice produced decreased IgG2a and very slightly increased IgG1 compared to controls at day 12
• splenic NK cells from mutants produce less Ifng in response to Il-12 or Il-18 than NK cells from wild-type
• NK cells from mutants are impaired in ability to lyse YAC-1 cells compared to wild-type
• NK cells from mutants treated with poly(I:C) for activation lyse tumor cell targets equivalently to wild-type NK cells
• increased amount of TGFb is found in bronchial alveolar lavage (BAL) fluid compared to wild-type
• increased amounts of Il-4 and Il-13 are found in BAL fluid; Il-5 levels are high in mutants and do not increase with allergen challenge as wild-type levels do
• increased amount of TNFa is found in bronchial alveolar lavage (BAL) fluid compared to wild-type
• anti-CD3 and -CD28 stimulated CD4 T cells from lymph nodes of mutants show marked decrease in Ifng (interferon-gamma) production compared to controls; in presence of Il-12, Ifng production is reduced as well
• homozygotes show peribronchial and perivenular infiltration with eosinophils and lymphocytes compared to wild-type littermates
• mutants on C57BL/6 background produce less Ifng in response to L. major infection and fail to cure infection, similar to BALB/c (susceptible) controls, while C57BL/6 (resistant) controls cure infection

respiratory system
• homozygotes show peribronchial and perivenular infiltration with eosinophils and lymphocytes compared to wild-type littermates
• mice show an increase in thickness of subbasement collagen layer of the airways, with an increased numbers of bronchial myofibroblast
• 4-5 week old homozygous mice exhibit airway hyperresponsiveness (AHR) to methacholine challenge, in the absence of prior immunologic sensitization; mice are more responsive without allergen challenge than wild-type mice following antigen challenge

homeostasis/metabolism
• increased amount of TGFb is found in bronchial alveolar lavage (BAL) fluid compared to wild-type
• increased amounts of Il-4 and Il-13 are found in BAL fluid; Il-5 levels are high in mutants and do not increase with allergen challenge as wild-type levels do
• increased amount of TNFa is found in bronchial alveolar lavage (BAL) fluid compared to wild-type

Mouse Models of Human Disease
OMIM IDRef(s)
Asthma, Susceptibility to 600807 J:73832


Mouse Genome Informatics
ht5
    Tbx21tm1Glm/Tbx21+
involves: 129S6/SvEvTac * C57BL/6
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
hematopoietic system
• only 42% of CD4 T cells produce high levels of Ifng compared to wild-type
• splenic NK cells from mutants produce less Ifng in response to Il-12 or Il-18 than NK cells from wild-type

immune system
• only 42% of CD4 T cells produce high levels of Ifng compared to wild-type
• splenic NK cells from mutants produce less Ifng in response to Il-12 or Il-18 than NK cells from wild-type
• increased amount of TGFb is found in bronchial alveolar lavage (BAL) fluid compared to wild-type
• increased amounts of Il-4 and Il-13 are found in BAL fluid; Il-5 levels are high in mutants and do not increase with allergen challenge as wild-type levels do
• increased amount of TNFa is found in bronchial alveolar lavage (BAL) fluid compared to wild-type

respiratory system
• mice show an increase in thickness of subbasement collagen layer of the airways, with an increased numbers of bronchial myofibroblast
• 4-5 week old homozygous mice exhibit airway hyperresponsiveness (AHR) to methacholine challenge, in the absence of prior immunologic sensitization; mice are more responsive without allergen challenge than wild-type mice following antigen challenge

homeostasis/metabolism
• increased amount of TGFb is found in bronchial alveolar lavage (BAL) fluid compared to wild-type
• increased amounts of Il-4 and Il-13 are found in BAL fluid; Il-5 levels are high in mutants and do not increase with allergen challenge as wild-type levels do
• increased amount of TNFa is found in bronchial alveolar lavage (BAL) fluid compared to wild-type

Mouse Models of Human Disease
OMIM IDRef(s)
Asthma, Susceptibility to 600807 J:73832


Mouse Genome Informatics
cn6
    Eomestm1.1Bflu/Eomestm1.1Bflu
Tbx21tm1Glm/Tbx21tm1Glm
Tg(Cd4-cre)1Cwi/0

involves: 129S6/SvEvTac * C57BL/6 * DBA/2 * SJL
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
hematopoietic system
• Th1 and Tc1 cells show a total lack of migration toward CXCL10
• CD44+ effector/memory T cells are reduced in both CD4+ and CD8+ T cells

immune system
• Th1 and Tc1 cells show a total lack of migration toward CXCL10
• CD44+ effector/memory T cells are reduced in both CD4+ and CD8+ T cells
• by CD8 cells cultured for 4 days under Th1 conditions
• when CD8+ T cells are cultured in Th17-polarizing conditions 3 fold more IL17 producing cells are produced
• when CD8+ T cells are cultured in Tc2-polarizing conditions 3 fold more IL4 producing cells are produced

tumorigenesis
• 60% of mice vaccinated against B16 melenoma still grow tumors upon B16 injection

cellular
• Th1 and Tc1 cells show a total lack of migration toward CXCL10


Mouse Genome Informatics
cx7
    Rag2tm1Fwa/Rag2tm1Fwa
Tbx21tm1Glm/Tbx21tm1Glm

involves: 129S/SvEv * 129S6/SvEvTac
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
digestive/alimentary system
N
• despite developing spontaneous ulcerative colitis, mice exhibit normal stomachs and small intestines (J:141481)
• at 3.5 weeks, mice exhibit large epithelial discontinuities with a 4- to 5-fold increase in apoptosis of epithelial cells compared with wild-type or single homozygous mice
• however, treatment with anti-TNF-alpha antibodies normalizes the level of apoptosis
• mice exhibit crypt loss associated with the development of colitis
• mice exhibit anorectal prolapse unlike wild-type or single homozygous mice
• at 3.5 weeks, colonic epithelial barrier is 2-fold more permeable than in Rag2tm1Fwa homozygotes
• at 4 to 5 weeks, colonic epithelial barrier is increased 3-fold
• at 5 to 6 weeks, colonic epithelial barrier is increased 8.6-fold
• by 4 weeks, mice develop inflammation of the rectum and left colon unlike or single homozygous wild-type mice
• mice exhibit inflammatory infiltrate in the lamina propria, neutrophil infiltration of the crypt and surface epithelium, and epithelial injury with surface denudations and ulcerations associated with crypt loss and epithelial mucodepletion
• by 4 weeks of age, mice develop highly penetrant and severe colitis unlike wild-type or single homozygous mice that increases in severity over time
• at 8 weeks, mice exhibit marked inflammation and colonic thickening unlike Rag2tm1Fwa homozygotes
• however, treatment with anti-TNF-alpha antibodies, T regulatory cells, or broad spectrum antibiotics restores normal colon phenotype, and treatment with broad spectrum antibiotics prevents communication of colitis to offspring
• female mice cross-fostering wild-type mice and Rag2tm1Fwa homozygotes fail to establish normal resistance to colitis in cross-fostered pups and mice can transmit susceptibility to colitis to wild-type mice housemates

immune system
• by 4 weeks, mice develop inflammation of the rectum and left colon unlike or single homozygous wild-type mice
• mice exhibit inflammatory infiltrate in the lamina propria, neutrophil infiltration of the crypt and surface epithelium, and epithelial injury with surface denudations and ulcerations associated with crypt loss and epithelial mucodepletion
• by 4 weeks of age, mice develop highly penetrant and severe colitis unlike wild-type or single homozygous mice that increases in severity over time
• at 8 weeks, mice exhibit marked inflammation and colonic thickening unlike Rag2tm1Fwa homozygotes
• however, treatment with anti-TNF-alpha antibodies, T regulatory cells, or broad spectrum antibiotics restores normal colon phenotype, and treatment with broad spectrum antibiotics prevents communication of colitis to offspring
• female mice cross-fostering wild-type mice and Rag2tm1Fwa homozygotes fail to establish normal resistance to colitis in cross-fostered pups and mice can transmit susceptibility to colitis to wild-type mice housemates
• as early as 2 weeks, colonic dendritic cells produce more TNF-alpha than wild-type cells
• in culture, bone marrow-derived dendritic cells produce more TNF-alpha compared with wild-type cells
• however, treatment with T regulatory cells reduced TNF-alpha levels

endocrine/exocrine glands
• mice exhibit crypt loss associated with the development of colitis


Mouse Genome Informatics
cx8
    Ldlrtm1Her/Ldlrtm1Her
Tbx21tm1Glm/Tbx21tm1Glm

involves: 129S6/SvEvTac * 129S7/SvEvBrd * C57BL/6
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype

Phenotype of aortic arch atherosclerotic lesions in Tbx21tm1Glm/Tbx21tm1Glm Ldlrtm1Her/Ldlrtm1Her and Ldlrtm1Her/Ldlrtm1Her mice

cardiovascular system
• atherosclerosis in both aortic arch and descending aorta is significantly reduced compared with Ldlrtm1Her homozygotes and lesions have less smooth muscle content
• males have an 81% reduction in the aortic arch intimal area of lesions and 49% reduction in descending aorta compared with control males, however no differences seen in females
• after 8 weeks of proatherogenic diet, intimal smooth muscle cell content is lower in aortic arch than in controls, indicating a delay in evolution of lesions

homeostasis/metabolism
• hypercholesterolemic; cholesterol levels are no different from those in Ldlrtm1Her homozygotes

immune system
• significant reduction of total IgG2a compared to Ldlrtm1Her homozygotes; IgG2a titers to both MDA-LDL and CuOx-LDL are reduced or absent
• IgG1 titers to both antigens (MDA-LDL and CuOx-LDL) are reduced despite similar total levels of IgG1
• exhibit a more than 2.5-fold increase in the titer of atheroprotective E06 natural IgM antibodies compared to Ldlrtm1Her homozygotes
• unlike CD4+ T cells in Ldlrtm1Her homozygotes on a high cholesterol diet, T cells do not produce significant amounts of IFN-gamma upon polyclonal stimulation with anti-CD3 and upon stimulation with plaque antigen hsp60
• on a high cholesterol diet, higher levels of IL-4, IL-5, and IL-10 are produced upon anti-CD3 stimulation and higher levels of IL-5 and IL-10 upon hsp60 stimulation of T cells compared to T cells from Ldlrtm1Her homozygotes

hematopoietic system
• significant reduction of total IgG2a compared to Ldlrtm1Her homozygotes; IgG2a titers to both MDA-LDL and CuOx-LDL are reduced or absent
• IgG1 titers to both antigens (MDA-LDL and CuOx-LDL) are reduced despite similar total levels of IgG1
• exhibit a more than 2.5-fold increase in the titer of atheroprotective E06 natural IgM antibodies compared to Ldlrtm1Her homozygotes


Mouse Genome Informatics
cx9
    Tbx21tm1Glm/Tbx21tm1Glm
Tg(TRAMP)8247Ng/0

involves: 129S6/SvEvTac * C57BL/6
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
tumorigenesis
• Tbx21-deficient transgenic mice consistently develop increased frequency of metastatic disease in the liver, lung or salivary glands (3/21 Tbx21-sufficient vs 13/25 Tbx21-null transgenics) (J:88093)
• per organ, tissues develop higher rates of metastasis(24% of 88 organs) vs Tbx21-sufficient transgenic mice (6% of 79 organs); metastasis is not seen in non-transgenic Tbx21-sufficient animals but was observed in 1 non-transgenic Tbx21-null mouse with low grade prostatic adenocarcinoma (J:88093)
• mice aged 21-30 weeks of age develop primary prostate cancers; frequency is comparable to Tbx21-sufficient transgenic mice (J:88093)
• all mice regardless of Tbx21 status develop high-grade prostatic epithelial neoplasia with 96% of Tbx21-sufficient vs 91% of Tbx21-deficient transgenic mice developing overt adenocarcinoma (J:88093)
• Tbx21-deficient transgenics develop a modest but somewhat higher grade adenocarcinomas than Tbx21-sufficient mice (J:88093)
• overall tumor size does not differ significantly between genotypes (J:88093)