Description

Strain Information

Type Congenic; Mutant Strain; 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)   21-MAR-12 Species laboratory mouse Generation N14+F8 (21-OCT-12) Generation Definitions   Donating Investigator Nigel Killeen,   Univ of California San Francisco (UCSF)

Description
In Ox40^-/- mice, the targeted mutation replaces exons 1-4 of the tumor necrosis factor receptor superfamily, member 4 (Tnfrsf4 or Ox40) locus with a floxed neomycin (neo) resistance cassette, abolishing gene function. Homozygous mice are viable, fertile, and normal in size. Ox40^-/- CD4⁺ T cells Ox40-/- CD4+ T cells demonstrate defects in clonal expansion associated with impaired survival of activated cells. These mice may be useful for studying the importance of the CD134 molecule in T cell differentiation and responses.

Development
A targeting vector was designed to replace exons 1-4 encoding the tumor necrosis factor receptor superfamily, member 4 (Tnfrsf4 or Ox40) locus with a floxed neomycin resistance (neo) cassette. The construct was electroporated into 129S4/SvJae-derived RF8 embryonic stem (ES) cells. Correctly targeted ES cells were injected into C57BL/6 blastocysts and the resulting chimeric males were bred to C57BL/6 females. These mice were then intercrossed to produce Ox40^-/- mice and were subsequently backcrossed at least 13 generations to C57BL/6 mice. Upon arrival at The Jackson Laboratory, mice were bred to C57BL/6J (Stock No. 000664) for at least one generation to establish the colony.

Control Information

	Control
	000664 C57BL/6J	(approximate)
Considerations for Choosing Controls

Related Strains

Strains carrying other alleles of Tnfrsf4

012839

B6.129X1(Cg)-Tnfrsf4tm2(cre)Nik/J

View Strains carrying other alleles of Tnfrsf4     (1 strain)

Strains carrying other alleles of neo

010633	B6(Cg)-Gt(ROSA)26Sortm1(CAG-taulacZ)Bene/J
012247	B6.129-Aldh1a1tm1Gdu/J
006382	B6;129-Casktm1Sud/J
016857	B6;129-Itga7tm1Burk/J
010711	C57BL/6-Ptrh2tm1Eruo/J
002356	C57BL/6J-Tg(pPGKneobpA)3Ems/J
009063	STOCK Ednrbtm1Nrd/J
012940	STOCK Snta1tm1Scf/J
003208	STOCK Tg(DR4)1Jae/J

View Strains carrying other alleles of neo     (9 strains)

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.

Tnfrsf4^tm1Nik/Tnfrsf4^tm1Nik

        involves: 129S4/SvJae * C57BL/6

• immune system phenotype
• *normal* immune system phenotype
  • primary and secondary lymphoid tissues had normal cellularity, expression of lymphocyte differentiation markers, and presence of germinal centers   (MGI Ref ID J:58979)
  • normal response to infection by: Leishmania major, Nippostrongylus brasiliensis, and Theiler's murine encephalomyelitis   (MGI Ref ID J:58979)
  • normal antibody response to various antigens   (MGI Ref ID J:58979)
  • normal response in delayed-type hypersensitivity reactions using oxazolone   (MGI Ref ID J:58979)
• • abnormal CD4-positive T cell physiology
    • primary and memory responses impaired in response to keyhole limpet hemocyanin immunization: decreased production of antigen-specific CD4+ cells and memory cells and decreased proliferation, decreased production of cytokines (IL2, IFN-gamma, IL5, IL4), at both 7 days and 35 days post-immunization   (MGI Ref ID J:64552)
  • • abnormal T-helper 2 physiology
      • impaired ability to mount Th2 response in ovalbumin model of asthma, characterized by lack of production of: IL5, IL4, IgE   (MGI Ref ID J:68588)
  • decreased T cell proliferation
    • in response to anti-CD3 epsilon antibodies, but not in mixed lymphocyte reactions, peptide specific response, or stimulation with staphylococcal enterotoxin B   (MGI Ref ID J:58979)
    • in response to anti-CD3 epsilon antibodies over the course of 5 days   (MGI Ref ID J:64552)
    • corresponding decline in T cell survival over this time   (MGI Ref ID J:64552)
    • declines in IL2 production corresponded to declines in proliferation and survival   (MGI Ref ID J:64552)
  • decreased susceptibility to type I hypersensitivity reaction
    • in response to ovalbumin model of asthma, characterized by decreased lung inflammation, especially with lack of eosinophilia, decreased mucus production, decreased goblet cell hyperplasia and decreased airway hyperreactivity   (MGI Ref ID J:68588)
• hematopoietic system phenotype
• decreased T cell proliferation
  • in response to anti-CD3 epsilon antibodies, but not in mixed lymphocyte reactions, peptide specific response, or stimulation with staphylococcal enterotoxin B   (MGI Ref ID J:58979)
  • in response to anti-CD3 epsilon antibodies over the course of 5 days   (MGI Ref ID J:64552)
  • corresponding decline in T cell survival over this time   (MGI Ref ID J:64552)
  • declines in IL2 production corresponded to declines in proliferation and survival   (MGI Ref ID J:64552)
• cellular phenotype
• decreased T cell proliferation
  • in response to anti-CD3 epsilon antibodies, but not in mixed lymphocyte reactions, peptide specific response, or stimulation with staphylococcal enterotoxin B   (MGI Ref ID J:58979)
  • in response to anti-CD3 epsilon antibodies over the course of 5 days   (MGI Ref ID J:64552)
  • corresponding decline in T cell survival over this time   (MGI Ref ID J:64552)
  • declines in IL2 production corresponded to declines in proliferation and survival   (MGI Ref ID J:64552)

View Research Applications

Research Applications

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

Research Tools
Immunology and Inflammation Research
      T Cell Receptor Deficiency

neo related

Research Tools
Genetics Research
      Mutagenesis and Transgenesis
      Mutagenesis and Transgenesis: Production of Targeted Mutations (Knockouts), feeder cells for ES cell lines

Genes & Alleles

Gene & Allele Information provided by MGI

Allele Symbol		Tnfrsf4tm1Nik
Allele Name		targeted mutation 1, Nigel Killeen
Allele Type		Targeted (knock-out)
Common Name(s)		CD134-; OX40 KO; OX40-;
Mutation Made By		Nigel Killeen,   Univ of California San Francisco (UCSF)
Strain of Origin		129S4/SvJae
Expressed Gene		neo, neomycin resistance, bacterial
Molecular Note		A neomycin cassette was used to replace four exons, which code for the first 143 amino acids of the protein. Activated T cells from homozygous mutant animals lacked expression of Tnfrsf4 as detected by flow cytometry with the OX86 mAb as well as a soluable ligand fusion protein. [MGI Ref ID J:58979]
Gene Symbol and Name		Tnfrsf4, tumor necrosis factor receptor superfamily, member 4
Chromosome		4
Gene Common Name(s)		ACT35; CD134; OX40; Ox-40 T-cell antigen; Ox40; TXGP1L; Txgp1; tax-transcriptionally activated glycoprotein 1;

Genotyping

Genotyping Information

Genotyping Protocols

Tnfrsf4^tm1Nik, Standard PCR

Helpful Links

Genotyping resources and troubleshooting

References

References provided by MGI

Selected Reference(s)

Pippig SD; Pena-Rossi C; Long J; Godfrey WR; Fowell DJ; Reiner SL; Birkeland ML; Locksley RM; Barclay AN; Killeen N. 1999. Robust B cell immunity but impaired T cell proliferation in the absence of CD134 (OX40). J Immunol 163(12):6520-9. [PubMed: 10586044]  [MGI Ref ID J:58979]

Additional References

Tnfrsf4^tm1Nik related

Bansal-Pakala P; Halteman BS; Cheng MH; Croft M. 2004. Costimulation of CD8 T cell responses by OX40. J Immunol 172(8):4821-5. [PubMed: 15067059]  [MGI Ref ID J:89135]

Burocchi A; Pittoni P; Gorzanelli A; Colombo MP; Piconese S. 2011. Intratumor OX40 stimulation inhibits IRF1 expression and IL-10 production by Treg cells while enhancing CD40L expression by effector memory T cells. Eur J Immunol 41(12):3615-26. [PubMed: 22229156]  [MGI Ref ID J:179655]

Duan W; So T; Croft M. 2008. Antagonism of airway tolerance by endotoxin/lipopolysaccharide through promoting OX40L and suppressing antigen-specific Foxp3+ T regulatory cells. J Immunol 181(12):8650-9. [PubMed: 19050285]  [MGI Ref ID J:142054]

Gough MJ; Ruby CE; Redmond WL; Dhungel B; Brown A; Weinberg AD. 2008. OX40 agonist therapy enhances CD8 infiltration and decreases immune suppression in the tumor. Cancer Res 68(13):5206-15. [PubMed: 18593921]  [MGI Ref ID J:138877]

Gramaglia I; Jember A; Pippig SD; Weinberg AD; Killeen N; Croft M. 2000. The OX40 costimulatory receptor determines the development of CD4 memory by regulating primary clonal expansion J Immunol 165(6):3043-50. [PubMed: 10975814]  [MGI Ref ID J:64552]

Gri G; Piconese S; Frossi B; Manfroi V; Merluzzi S; Tripodo C; Viola A; Odom S; Rivera J; Colombo MP; Pucillo CE. 2008. CD4+CD25+ regulatory T cells suppress mast cell degranulation and allergic responses through OX40-OX40L interaction. Immunity 29(5):771-81. [PubMed: 18993084]  [MGI Ref ID J:143181]

Griseri T; Asquith M; Thompson C; Powrie F. 2010. OX40 is required for regulatory T cell-mediated control of colitis. J Exp Med 207(4):699-709. [PubMed: 20368580]  [MGI Ref ID J:161661]

Humphreys IR; Loewendorf A; de Trez C; Schneider K; Benedict CA; Munks MW; Ware CF; Croft M. 2007. OX40 costimulation promotes persistence of cytomegalovirus-specific CD8 T Cells: A CD4-dependent mechanism. J Immunol 179(4):2195-202. [PubMed: 17675479]  [MGI Ref ID J:151228]

Jember AG; Zuberi R; Liu FT; Croft M. 2001. Development of allergic inflammation in a murine model of asthma is dependent on the costimulatory receptor OX40. J Exp Med 193(3):387-92. [PubMed: 11157058]  [MGI Ref ID J:68588]

Kroemer A; Xiao X; Vu MD; Gao W; Minamimura K; Chen M; Maki T; Li XC. 2007. OX40 controls functionally different T cell subsets and their resistance to depletion therapy. J Immunol 179(8):5584-91. [PubMed: 17911646]  [MGI Ref ID J:153016]

Magalhaes JG; Rubino SJ; Travassos LH; Le Bourhis L; Duan W; Sellge G; Geddes K; Reardon C; Lechmann M; Carneiro LA; Selvanantham T; Fritz JH; Taylor BC; Artis D; Mak TW; Comeau MR; Croft M; Girardin SE; Philpott DJ. 2011. Nucleotide oligomerization domain-containing proteins instruct T cell helper type 2 immunity through stromal activation. Proc Natl Acad Sci U S A 108(36):14896-901. [PubMed: 21856952]  [MGI Ref ID J:175223]

Piconese S; Valzasina B; Colombo MP. 2008. OX40 triggering blocks suppression by regulatory T cells and facilitates tumor rejection. J Exp Med 205(4):825-39. [PubMed: 18362171]  [MGI Ref ID J:134000]

Redmond WL; Gough MJ; Weinberg AD. 2009. Ligation of the OX40 co-stimulatory receptor reverses self-Ag and tumor-induced CD8 T-cell anergy in vivo. Eur J Immunol 39(8):2184-94. [PubMed: 19672905]  [MGI Ref ID J:151937]

Redmond WL; Triplett T; Floyd K; Weinberg AD. 2012. Dual anti-OX40/IL-2 therapy augments tumor immunotherapy via IL-2R-mediated regulation of OX40 expression. PLoS One 7(4):e34467. [PubMed: 22496812]  [MGI Ref ID J:187106]

Rogers PR; Song J; Gramaglia I; Killeen N; Croft M. 2001. OX40 promotes Bcl-xL and Bcl-2 expression and is essential for long-term survival of CD4 T cells. Immunity 15(3):445-55. [PubMed: 11567634]  [MGI Ref ID J:71803]

Salek-Ardakani S; Moutaftsi M; Crotty S; Sette A; Croft M. 2008. OX40 drives protective vaccinia virus-specific CD8 T cells. J Immunol 181(11):7969-76. [PubMed: 19017988]  [MGI Ref ID J:142375]

So T; Croft M. 2007. Cutting edge: OX40 inhibits TGF-beta- and antigen-driven conversion of naive CD4 T cells into CD25+Foxp3+ T cells. J Immunol 179(3):1427-30. [PubMed: 17641007]  [MGI Ref ID J:149955]

So T; Soroosh P; Eun SY; Altman A; Croft M. 2011. Antigen-independent signalosome of CARMA1, PKC{theta}, and TNF receptor-associated factor 2 (TRAF2) determines NF-{kappa}B signaling in T cells. Proc Natl Acad Sci U S A 108(7):2903-8. [PubMed: 21282629]  [MGI Ref ID J:169068]

Song A; Song J; Tang X; Croft M. 2007. Cooperation between CD4 and CD8 T cells for anti-tumor activity is enhanced by OX40 signals. Eur J Immunol 37(5):1224-32. [PubMed: 17429847]  [MGI Ref ID J:123581]

Song A; Tang X; Harms KM; Croft M. 2005. OX40 and Bcl-xL promote the persistence of CD8 T cells to recall tumor-associated antigen. J Immunol 175(6):3534-41. [PubMed: 16148096]  [MGI Ref ID J:129686]

Song J; Salek-Ardakani S; Rogers PR; Cheng M; Van Parijs L; Croft M. 2004. The costimulation-regulated duration of PKB activation controls T cell longevity. Nat Immunol 5(2):150-8. [PubMed: 14730361]  [MGI Ref ID J:87871]

Song J; So T; Croft M. 2008. Activation of NF-kappaB1 by OX40 contributes to antigen-driven T cell expansion and survival. J Immunol 180(11):7240-8. [PubMed: 18490723]  [MGI Ref ID J:136337]

Tang Q; Henriksen KJ; Boden EK; Tooley AJ; Ye J; Subudhi SK; Zheng XX; Strom TB; Bluestone JA. 2003. Cutting edge: CD28 controls peripheral homeostasis of CD4+CD25+ regulatory T cells. J Immunol 171(7):3348-52. [PubMed: 14500627]  [MGI Ref ID J:120383]

Vasilevsky NA; Ruby CE; Hurlin PJ; Weinberg AD. 2011. OX40 engagement stabilizes Mxd4 and Mnt protein levels in antigen-stimulated T cells leading to an increase in cell survival. Eur J Immunol 41(4):1024-34. [PubMed: 21400495]  [MGI Ref ID J:177017]

Vu MD; Xiao X; Gao W; Degauque N; Chen M; Kroemer A; Killeen N; Ishii N; Chang Li X. 2007. OX40 costimulation turns off Foxp3+ Tregs. Blood 110(7):2501-10. [PubMed: 17575071]  [MGI Ref ID J:147020]

Xiao X; Balasubramanian S; Liu W; Chu X; Wang H; Taparowsky EJ; Fu YX; Choi Y; Walsh MC; Li XC. 2012. OX40 signaling favors the induction of T(H)9 cells and airway inflammation. Nat Immunol 13(10):981-90. [PubMed: 22842344]  [MGI Ref ID J:187731]

Xiao X; Gong W; Demirci G; Liu W; Spoerl S; Chu X; Bishop DK; Turka LA; Li XC. 2012. New insights on OX40 in the control of T cell immunity and immune tolerance in vivo. J Immunol 188(2):892-901. [PubMed: 22147766]  [MGI Ref ID J:180889]

Xiao X; Kroemer A; Gao W; Ishii N; Demirci G; Li XC. 2008. OX40/OX40L costimulation affects induction of Foxp3+ regulatory T cells in part by expanding memory T cells in vivo. J Immunol 181(5):3193-201. [PubMed: 18713990]  [MGI Ref ID J:138954]

Health & husbandry

Health & Colony Maintenance Information

Animal Health Reports

Room Number           AX11

Colony Maintenance

Breeding & Husbandry	When maintaining a live colony, homozygous mice may be bred together.
Mating System	Homozygote x Homozygote         (Female x Male)   21-MAR-12
Diet Information	LabDiet® 5K52/5K67

Pricing and Purchasing

Pricing, Supply Level & Notes, Controls

Control Information

	Control
	000664 C57BL/6J	(approximate)
Considerations for Choosing Controls
Control Pricing Information for Genetically Engineered Mutant Strains.

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Terms are granted by individual review and stated on the customer invoice(s) and account statement. These transactions are payable in U.S. currency within the granted terms. Payment for services, products, shipping containers, and shipping costs that are rendered are expected within the payment terms indicated on the invoice or stated by contract. Invoices and account balances in arrears of stated terms may result in The Jackson Laboratory pursuing collection activities including but not limited to outside agencies and court filings.

See Terms of Use tab for General Terms and Conditions

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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