Description

Strain Information

Former Names B6.129-Ebi3tm1Rsb/J    (Changed: 05-NOV-08 ) Type Congenic; Targeted Mutation; Additional information on Genetically Engineered and Mutant Mice. Visit our online Nomenclature tutorial. Additional information on Congenic nomenclature. Mating System Homozygote x Homozygote         (Female x Male)   29-DEC-09 Species laboratory mouse Generation N10+F7 (28-DEC-12) Generation Definitions   Donating Investigator Richard S Blumberg,   Brigham and Women's Hospital

Description
Mice homozygous for this Ebi3-mutant allele are viable and fertile with the donating investigator reporting no overt autoimmunity or inflammatory disease associated with the mutation. No RNA from the targeted gene is observed in splenocytes isolated from homozygotes. Ebi3-deficiency leads to impaired T_reg activity with failure to control homeostatic proliferation. Homozygotes exhibit decreased numbers and function of invariant natural killer T cells (iNKT); stimulated iNKT cells show impaired IL-4 production both in vivo and in vitro. Homozygotes are resistant to oxazolone-induced colitis (mediated primarily by T helper (Th) 2-type cytokine production by iNKT cells), whereas Ebi3-deficiency shows no affect on trinitrobenzene sulfonic acid-induced colitis (a predominantly Th1-mediated colitis model). These Ebi3-mutant strains may be useful in studying T_reg function, IL12 heterodimeric cytokines (such as IL-35 and IL-27),IFNgamma production, and Th1/Th2 immune responses (including inflammatory bowel disease).

Of note, Ebi3-mutant mice are also be available on a BALB/c congenic background (see Stock No. 008701).

In an attempt to offer alleles on well-characterized or multiple genetic backgrounds, alleles are frequently moved to a genetic background different from that on which an allele was first characterized. It should be noted that the phenotype could vary from that originally described. We will modify the strain description if necessary as published results become available.

Development
The targeting vector was designed to replace exons 2-5 (encoding amino acids 24-228) of the targeted gene with a PGK-Neo cassette. The donating investigators lab reports that the construct was electroporated into 129X1/SvJ-derived RW4 embryonic stem (ES) cells. Correctly targeted ES cells were injected into blastocysts and offspring from the resulting chimeric mice were bred to C57BL/6NCrl inbred mice. Ebi3-mutant mice were then backcrossed to C57BL/6NCrl for at least 9 generations prior to arrival at The Jackson Laboratory. Upon arrival, mice were bred to C57BL/6NJ inbred mice (Stock No. 005304) for at least one generation to establish the current colony.

Control Information

	Control
	005304 C57BL/6NJ	(approximate)
Considerations for Choosing Controls

Related Strains

Strains carrying   Ebi3^tm1Rsb allele

008701

C.129X1(B6)-Ebi3tm1Rsb/J

View Strains carrying   Ebi3^tm1Rsb     (1 strain)

Phenotype

Phenotype Information

View Mammalian Phenotype Terms

Mammalian Phenotype Terms provided by MGI

      assigned by genotype

The following phenotype information may relate to a genetic background differing from this JAX^® Mice strain.

Ebi3^tm1Rsb/Ebi3^tm1Rsb

        involves: 129X1/SvJ * C57BL/6

• immune system phenotype
• abnormal immune system morphology   (MGI Ref ID J:81014)
• • abnormal T-helper 1 cell morphology
    • proportion of Th1 cells increases later in parasitic infections when the infection is resolving   (MGI Ref ID J:97822)
  • abnormal T-helper 2 cell morphology
    • proportion of Th2 is higher early in parasitic infects but not later   (MGI Ref ID J:97822)
  • • decreased T-helper 2 cell number
      • lower portion of Th2 cells although levels can be stimulated to normal   (MGI Ref ID J:81014)
  • decreased NK cell number
    • statistically significant reduction in invariant natural killer cells in the liver   (MGI Ref ID J:81014)
    • remaining natural killer cells have a reduced ability to produce IL-4   (MGI Ref ID J:81014)
• abnormal immune system physiology   (MGI Ref ID J:81014)
• • decreased interleukin-4 secretion
    • after stimulation of CD4+ cells, lower production of IL-4 than in controls   (MGI Ref ID J:81014)
    • serum levels of IL-4 are undetectable after stimulation   (MGI Ref ID J:81014)
  • decreased susceptibility to induced colitis
    • resistant to Th2 mediated oxazolone-induced colitis   (MGI Ref ID J:81014)
    • Th1 mediated colitis proceeds normally   (MGI Ref ID J:81014)
  • increased interferon-gamma secretion
    • unstimulated CD4+ cells produce moderately increased levels of IFN-gamma   (MGI Ref ID J:81014)
    • levels after stimulation are less than controls 2-4 hours after stimulation but reach normal levels at 24 hours   (MGI Ref ID J:81014)
  • increased susceptibility to parasitic infection
    • enhanced susceptibility to Leishmania major at lower physiologically relevant doses   (MGI Ref ID J:97822)
    • larger lesions after L. major infection, 4X the size in controls at 6 week   (MGI Ref ID J:97822)
    • higher parasite burdens at site of infection, peaking at 6 weeks   (MGI Ref ID J:97822)
    • parasite level in spleens reaches 44X that of controls at 7 weeks but decreases after 8 weeks and infection is resolved by 14 weeks   (MGI Ref ID J:97822)
• digestive/alimentary phenotype
• decreased susceptibility to induced colitis
  • resistant to Th2 mediated oxazolone-induced colitis   (MGI Ref ID J:81014)
  • Th1 mediated colitis proceeds normally   (MGI Ref ID J:81014)
• hematopoietic system phenotype
• abnormal T-helper 1 cell morphology
  • proportion of Th1 cells increases later in parasitic infections when the infection is resolving   (MGI Ref ID J:97822)
• abnormal T-helper 2 cell morphology
  • proportion of Th2 is higher early in parasitic infects but not later   (MGI Ref ID J:97822)
• • decreased T-helper 2 cell number
    • lower portion of Th2 cells although levels can be stimulated to normal   (MGI Ref ID J:81014)
• decreased NK cell number
  • statistically significant reduction in invariant natural killer cells in the liver   (MGI Ref ID J:81014)
  • remaining natural killer cells have a reduced ability to produce IL-4   (MGI Ref ID J:81014)

View Research Applications

Research Applications

This mouse can be used to support research in many areas including:

Cancer Research
Genes Regulating Growth and Proliferation
Growth Factors/Receptors/Cytokines

Cell Biology Research
Genes Regulating Growth and Proliferation

Immunology, Inflammation and Autoimmunity Research
CD Antigens, Antigen Receptors, and Histocompatibility Markers
      genes regulating susceptibility to infectious disease and endotoxin
Growth Factors/Receptors/Cytokines
Immunodeficiency
      Inflammatory bowel disease
      T cell deficiency
      specific T cell deficiency
Inflammation
      Inflammatory bowel disease
Intracellular Signaling Molecules

Internal/Organ Research
Gastrointestinal Defects
      colitis
Lymphoid Tissue Defects
      T cell deficiency

Research Tools
Cancer Research
      T cell deficiency
      specific T cell deficiency
Immunology and Inflammation Research
      T cell deficiency
      genes regulating susceptibility to infectious disease and endotoxin
      specific T cell deficiency

Genes & Alleles

Gene & Allele Information provided by MGI

Allele Symbol		Ebi3tm1Rsb
Allele Name		targeted mutation 1, Richard Blumberg
Allele Type		Targeted (knock-out)
Common Name(s)		EBI-3; EBI3-; EBI3tm Birk; Ebi3tm1Birk;
Mutation Made By		Richard Blumberg,   Brigham and Women's Hospital
Strain of Origin		129X1/SvJ
ES Cell Line Name		RW-4
ES Cell Line Strain		129X1/SvJ
Gene Symbol and Name		Ebi3, Epstein-Barr virus induced gene 3
Chromosome		17
Gene Common Name(s)		EBI-3; IL-27; IL-27B; IL27B;
Molecular Note		Sequence encompassing exons 2 through 5 was replaced by a neomycin selection cassette inserted by homologous recombination. Northern blot analysis of splenic RNA indicated an absence of normal transcript in homozygous mutant mice. [MGI Ref ID J:81014]

Genotyping

Genotyping Information

Genotyping Protocols

Ebi3^tm1Rsb MCA, Melt Curve Analysis
Ebi3^tm1Rsb, Standard PCR

Helpful Links

Genotyping resources and troubleshooting

References

References provided by MGI

Selected Reference(s)

Collison LW; Workman CJ; Kuo TT; Boyd K; Wang Y; Vignali KM; Cross R; Sehy D; Blumberg RS; Vignali DA. 2007. The inhibitory cytokine IL-35 contributes to regulatory T-cell function. Nature 450(7169):566-9. [PubMed: 18033300]  [MGI Ref ID J:127800]

Nieuwenhuis EE; Neurath MF; Corazza N; Iijima H; Trgovcich J; Wirtz S; Glickman J; Bailey D; Yoshida M; Galle PR; Kronenberg M; Birkenbach M; Blumberg RS. 2002. Disruption of T helper 2-immune responses in Epstein-Barr virus-induced gene 3-deficient mice. Proc Natl Acad Sci U S A 99(26):16951-6. [PubMed: 12482940]  [MGI Ref ID J:81014]

Additional References

Ebi3^tm1Rsb related

Cobb D; Smeltz RB. 2012. Regulation of proinflammatory Th17 responses during Trypanosoma cruzi infection by IL-12 family cytokines. J Immunol 188(8):3766-73. [PubMed: 22412196]  [MGI Ref ID J:184072]

Collison LW; Chaturvedi V; Henderson AL; Giacomin PR; Guy C; Bankoti J; Finkelstein D; Forbes K; Workman CJ; Brown SA; Rehg JE; Jones ML; Ni HT; Artis D; Turk MJ; Vignali DA. 2010. IL-35-mediated induction of a potent regulatory T cell population. Nat Immunol 11(12):1093-101. [PubMed: 20953201]  [MGI Ref ID J:167328]

Collison LW; Pillai MR; Chaturvedi V; Vignali DA. 2009. Regulatory T cell suppression is potentiated by target T cells in a cell contact, IL-35- and IL-10-dependent manner. J Immunol 182(10):6121-8. [PubMed: 19414764]  [MGI Ref ID J:150297]

Dokmeci E; Xu L; Robinson E; Golubets K; Bottomly K; Herrick CA. 2011. EBI3 deficiency leads to diminished T helper type 1 and increased T helper type 2 mediated airway inflammation. Immunology 132(4):559-66. [PubMed: 21255010]  [MGI Ref ID J:172100]

Hausding M; Karwot R; Scholtes P; Lehr HA; Wegmann M; Renz H; Galle PR; Birkenbach M; Neurath MF; Blumberg RS; Finotto S. 2007. Lung CD11c+ cells from mice deficient in Epstein-Barr virus-induced gene 3 (EBI-3) prevent airway hyper-responsiveness in experimental asthma. Eur J Immunol 37(6):1663-77. [PubMed: 17506035]  [MGI Ref ID J:123602]

Liu JQ; Liu Z; Zhang X; Shi Y; Talebian F; Carl JW Jr; Yu C; Shi FD; Whitacre CC; Trgovcich J; Bai XF. 2012. Increased Th17 and regulatory T cell responses in EBV-induced gene 3-deficient mice lead to marginally enhanced development of autoimmune encephalomyelitis. J Immunol 188(7):3099-106. [PubMed: 22387555]  [MGI Ref ID J:183091]

Liu Z; Liu JQ; Talebian F; Wu LC; Li S; Bai XF. 2013. IL-27 enhances the survival of tumor antigen-specific CD8(+) T cells and programs them into IL-10-producing, memory precursor-like effector cells. Eur J Immunol 43(2):468-79. [PubMed: 23225163]  [MGI Ref ID J:193049]

Matta BM; Raimondi G; Rosborough BR; Sumpter TL; Thomson AW. 2012. IL-27 production and STAT3-dependent upregulation of B7-H1 mediate immune regulatory functions of liver plasmacytoid dendritic cells. J Immunol 188(11):5227-37. [PubMed: 22508931]  [MGI Ref ID J:188752]

Obar JJ; Jellison ER; Sheridan BS; Blair DA; Pham QM; Zickovich JM; Lefrancois L. 2011. Pathogen-induced inflammatory environment controls effector and memory CD8+ T cell differentiation. J Immunol 187(10):4967-78. [PubMed: 21987662]  [MGI Ref ID J:179638]

Sauer KA; Maxeiner JH; Karwot R; Scholtes P; Lehr HA; Birkenbach M; Blumberg RS; Finotto S. 2008. Immunosurveillance of lung melanoma metastasis in EBI-3-deficient mice mediated by CD8+ T cells. J Immunol 181(9):6148-57. [PubMed: 18941205]  [MGI Ref ID J:140735]

Siebler J; Wirtz S; Frenzel C; Schuchmann M; Lohse AW; Galle PR; Neurath MF. 2008. Cutting edge: a key pathogenic role of IL-27 in T cell- mediated hepatitis. J Immunol 180(1):30-3. [PubMed: 18096999]  [MGI Ref ID J:130899]

Sun J; Dodd H; Moser EK; Sharma R; Braciale TJ. 2011. CD4(+) T cell help and innate-derived IL-27 induce Blimp-1-dependent IL-10 production by antiviral CTLs. Nat Immunol 12(4):327-34. [PubMed: 21297642]  [MGI Ref ID J:170347]

Wirtz S; Tubbe I; Galle PR; Schild HJ; Birkenbach M; Blumberg RS; Neurath MF. 2006. Protection from lethal septic peritonitis by neutralizing the biological function of interleukin 27. J Exp Med 203(8):1875-81. [PubMed: 16880260]  [MGI Ref ID J:124391]

Zahn S; Wirtz S; Birkenbach M; Blumberg RS; Neurath MF; von Stebut E. 2005. Impaired Th1 responses in mice deficient in Epstein-Barr virus-induced gene 3 and challenged with physiological doses of Leishmania major. Eur J Immunol 35(4):1106-12. [PubMed: 15756639]  [MGI Ref ID J:97822]

Health & husbandry

Health & Colony Maintenance Information

Animal Health Reports

Room Number           AX12

Colony Maintenance

Breeding & Husbandry	When maintaining a live colony, homozygous mice may be bred together.
Mating System	Homozygote x Homozygote         (Female x Male)   29-DEC-09
Diet Information	LabDiet® 5K52/5K67

Pricing and Purchasing

Pricing, Supply Level & Notes, Controls

Control Information

	Control
	005304 C57BL/6NJ	(approximate)
Considerations for Choosing Controls
Control Pricing Information for Genetically Engineered Mutant Strains.

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The Jackson Laboratory's Genotype Promise

The Jackson Laboratory has rigorous genetic quality control and mutant gene genotyping programs to ensure the genetic background of JAX^® Mice strains as well as the genotypes of strains with identified molecular mutations. JAX^® Mice strains are only made available to researchers after meeting our standards. However, the phenotype of each strain may not be fully characterized and/or captured in the strain data sheets. Therefore, we cannot guarantee a strain's phenotype will meet all expectations. To ensure that JAX^® Mice will meet the needs of individual research projects or when requesting a strain that is new to your research, we suggest ordering and performing tests on a small number of mice to determine suitability for your particular project.

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