Strain Name:

NOD.129S1(B6)-Icostm1Flv/J

Stock Number:

008376

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These mice carry a targeted deletion of 3 exons in the Icos (inducible T cell co-stimulator) gene. T cell activation and proliferation are defective in the absence of expression. Homozygous knockout mice show a greatly enhanced susceptibility to experimental autoimmune encephalomyelitis, indicating that the gene has a protective role in inflammatory autoimmune diseases. On the NOD background, the presence of protein is indispensable for the development of insulitis and hyperglycemia in NOD mice. This strain is useful in studies of the induction of the autoimmune process that leads to diabetes.

Description

The genotypes of the animals provided may not reflect those discussed in the strain description or the mating scheme utilized by The Jackson Laboratory prior to cryopreservation. Please inquire for possible genotypes for this specific strain.

Strain Information

Former Names NOD.129S6(B6)-Icostm1Flv/J    (Changed: 18-MAY-09 )
Type Congenic; Targeted Mutation;
Additional information on Genetically Engineered and Mutant Mice.
Visit our online Nomenclature tutorial.
Additional information on Congenic nomenclature.
Specieslaboratory mouse
GenerationN?pN1
Generation Definitions
 
Donating InvestigatorDr. Richard A. Flavell,   Yale University School of Medicine

Description
Mice that are homozygous for the targeted deletion are viable and fertile. T cell activation and proliferation are defective in the absence of expression. In addition, T cells from homozygotes fail to produce interleukin-4 when differentiated in vitro or when primed in vivo. ICOS is required for humoral immune responses after immunization with several antigens. Homozygous knockout mice show a greatly enhanced susceptibility to experimental autoimmune encephalomyelitis, indicating that the gene has a protective role in inflammatory autoimmune diseases. On the NOD background, the presence of protein is indispensable for the development of insulitis and hyperglycemia in NOD mice. In T cells, the deletion of the gene results in a decreased production of the Th1 cytokine IFN-gamma, whereas the numbers of regulatory T cells remained unchanged. This strain is useful in studies of the induction of the autoimmune process that leads to diabetes.

Development
A targeting construct, replacing three exons (encoding all of the amino-acid sequences except the leader peptide) with a neomycin resistance gene driven by the PGK promoter, was transfected into 129S1/Sv Oca2+ Tyr+ Kitl+-derived W9.5 embryonic stem (ES) cells. This line was crossed with C57BL/6 perhaps 1 or 2 generations before being backcrossed to NOD for 10 generations by the donating laboratory.

Control Information

  Control
   001976 NOD/ShiLtJ
 
  Considerations for Choosing Controls

Related Strains

Strains carrying   Icostm1Flv allele
007019   B6.129S1-Icostm1Flv/J
View Strains carrying   Icostm1Flv     (1 strain)

Strains carrying other alleles of Icos
004859   B6.129P2-Icostm1Mak/J
017605   C.129S4-Icostm1Shr/J
View Strains carrying other alleles of Icos     (2 strains)

Phenotype

Phenotype Information

View Related Disease (OMIM) Terms

Related Disease (OMIM) Terms provided by MGI
- Potential model based on gene homology relationships. Phenotypic similarity to the human disease has not been tested.
Immunodeficiency, Common Variable, 1; CVID1   (ICOS)
Immunodeficiency, Common Variable, 2; CVID2   (ICOS)
View Mammalian Phenotype Terms

Mammalian Phenotype Terms provided by MGI
      assigned by genotype

Icostm1Flv/Icos+

        NOD.129S1-Icostm1Flv
  • endocrine/exocrine gland phenotype
  • decreased pancreatic islet number   (MGI Ref ID J:131529)
  • insulitis
  • immune system phenotype
  • insulitis

Icostm1Flv/Icostm1Flv

        NOD.129S1-Icostm1Flv
  • immune system phenotype
  • *normal* immune system phenotype
    • development of lymphocytes is normal   (MGI Ref ID J:131529)
    • decreased IgG level   (MGI Ref ID J:131529)
    • decreased T cell number
      • the number of CD25+ and FoxP3+ CD4 T cells in the periphery and pancreatic draining lymph nodes is decreased 30% compared to in heterozygotes   (MGI Ref ID J:131529)
      • the frequency of IFN-gamma+ T cells is decreased compared to in heterozygous mice   (MGI Ref ID J:131529)
    • decreased autoantibody level
      • anti-GAD65 and anti-insulin antibodies are decreased 3- to 5-fold compared to in heterozygotes   (MGI Ref ID J:131529)
      • decreased anti-insulin autoantibody level
        • decreased 3- to 5-fold compared to in heterozygotes   (MGI Ref ID J:131529)
    • decreased interferon-gamma secretion
      • the frequency of IFN-gamma+ T cells is decreased compared to in heterozygous mice   (MGI Ref ID J:131529)
    • decreased susceptibility to autoimmune diabetes
      • after 60 weeks, no mice develop diabetes compared with 65% of heterozygotes and 75% in wild-type NOD mice   (MGI Ref ID J:131529)
    • insulitis
      • only a few mice develop marginal levels of inflammation of the islets   (MGI Ref ID J:131529)
  • endocrine/exocrine gland phenotype
  • *normal* endocrine/exocrine gland phenotype
    • mice exhibit normal numbers of pancreatic islets   (MGI Ref ID J:131529)
    • insulitis
      • only a few mice develop marginal levels of inflammation of the islets   (MGI Ref ID J:131529)
  • hematopoietic system phenotype
  • decreased IgG level   (MGI Ref ID J:131529)
  • decreased T cell number
    • the number of CD25+ and FoxP3+ CD4 T cells in the periphery and pancreatic draining lymph nodes is decreased 30% compared to in heterozygotes   (MGI Ref ID J:131529)
    • the frequency of IFN-gamma+ T cells is decreased compared to in heterozygous mice   (MGI Ref ID J:131529)
View Research Applications

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

Immunology, Inflammation and Autoimmunity Research
Autoimmunity
      Type 1 Diabetes

Genes & Alleles

Gene & Allele Information provided by MGI

 
Allele Symbol Icostm1Flv
Allele Name targeted mutation 1, Richard A Flavell
Allele Type Targeted (knock-out)
Common Name(s) ICOS-;
Mutation Made ByDr. Richard Flavell,   Yale University School of Medicine
Strain of Origin129S1/Sv-Oca2<+> Tyr<+> Kitl<+>
ES Cell Line NameW9.5/W95
ES Cell Line Strain129S1/Sv-Oca2<+> Tyr<+> Kitl<+>
Gene Symbol and Name Icos, inducible T cell co-stimulator
Chromosome 1
Gene Common Name(s) AILIM; CD278; CVID1;
Molecular Note The three exons for all of the amino acid coding sequence except the leader peptide were replaced with a PGK-neomycin resistance cassette. Absence of protein product was demonstrated immunologically. [MGI Ref ID J:87123]

Genotyping

Genotyping Information

Genotyping Protocols

Icostm1Flv, Separated PCR


Helpful Links

Genotyping resources and troubleshooting

References

References provided by MGI

Selected Reference(s)

Dong C; Juedes AE; Temann UA; Shresta S; Allison JP; Ruddle NH; Flavell RA. 2001. ICOS co-stimulatory receptor is essential for T-cell activation and function. Nature 409(6816):97-101. [PubMed: 11343121]  [MGI Ref ID J:87123]

Additional References

Icostm1Flv related

Ali M; Weinreich M; Balcaitis S; Cooper CJ; Fink PJ. 2003. Differential regulation of peripheral CD4+ T cell tolerance induced by deletion and TCR revision. J Immunol 171(11):6290-6. [PubMed: 14634147]  [MGI Ref ID J:132828]

Choi YS; Kageyama R; Eto D; Escobar TC; Johnston RJ; Monticelli L; Lao C; Crotty S. 2011. ICOS Receptor Instructs T Follicular Helper Cell versus Effector Cell Differentiation via Induction of the Transcriptional Repressor Bcl6. Immunity 34(6):932-46. [PubMed: 21636296]  [MGI Ref ID J:174012]

Chung Y; Nurieva R; Esashi E; Wang YH; Zhou D; Gapin L; Dong C. 2008. A critical role of costimulation during intrathymic development of invariant NK T cells. J Immunol 180(4):2276-83. [PubMed: 18250436]  [MGI Ref ID J:131999]

Clay BS; Shilling RA; Bandukwala HS; Moore TV; Cannon JL; Welcher AA; Weinstock JV; Sperling AI. 2009. Inducible costimulator expression regulates the magnitude of Th2-mediated airway inflammation by regulating the number of Th2 cells. PLoS One 4(11):e7525. [PubMed: 19888475]  [MGI Ref ID J:155428]

Dong C; Temann UA; Flavell RA. 2001. Cutting edge: critical role of inducible costimulator in germinal center reactions. J Immunol 166(6):3659-62. [PubMed: 11238604]  [MGI Ref ID J:126655]

Ellyard JI; Chia T; Rodriguez-Pinilla SM; Martin JL; Hu X; Navarro-Gonzalez M; Garcia JF; Delfau-Larue MH; Montes-Moreno S; Gaulard P; Cook MC; Walters G; Piris MA; Vinuesa CG. 2012. Heterozygosity for Roquinsan leads to angioimmunoblastic T-cell lymphoma-like tumors in mice. Blood 120(4):812-21. [PubMed: 22700722]  [MGI Ref ID J:189087]

Guo F; Iclozan C; Suh WK; Anasetti C; Yu XZ. 2008. CD28 controls differentiation of regulatory T cells from naive CD4 T cells. J Immunol 181(4):2285-91. [PubMed: 18684917]  [MGI Ref ID J:140198]

Hawiger D; Tran E; Du W; Booth CJ; Wen L; Dong C; Flavell RA. 2008. ICOS mediates the development of insulin-dependent diabetes mellitus in nonobese diabetic mice. J Immunol 180(5):3140-7. [PubMed: 18292537]  [MGI Ref ID J:131529]

Hubbard VM; Eng JM; Ramirez-Montagut T; Tjoe KH; Muriglan SJ; Kochman AA; Terwey TH; Willis LM; Schiro R; Heller G; Murphy GF; Liu C; Alpdogan O; van den Brink MR. 2005. Absence of inducible costimulator on alloreactive T cells reduces graft versus host disease and induces Th2 deviation. Blood 106(9):3285-92. [PubMed: 15956289]  [MGI Ref ID J:123907]

Kornete M; Sgouroudis E; Piccirillo CA. 2012. ICOS-dependent homeostasis and function of Foxp3+ regulatory T cells in islets of nonobese diabetic mice. J Immunol 188(3):1064-74. [PubMed: 22227569]  [MGI Ref ID J:181217]

Linterman MA ; Rigby RJ ; Wong R ; Silva D ; Withers D ; Anderson G ; Verma NK ; Brink R ; Hutloff A ; Goodnow CC ; Vinuesa CG. 2009. Roquin differentiates the specialized functions of duplicated T cell costimulatory receptor genes CD28 and ICOS. Immunity 30(2):228-41. [PubMed: 19217324]  [MGI Ref ID J:146622]

Lischke T; Hegemann A; Gurka S; Vu Van D; Burmeister Y; Lam KP; Kershaw O; Mollenkopf HJ; Mages HW; Hutloff A; Kroczek RA. 2012. Comprehensive analysis of CD4+ T cells in the decision between tolerance and immunity in vivo reveals a pivotal role for ICOS. J Immunol 189(1):234-44. [PubMed: 22661090]  [MGI Ref ID J:188938]

Loke P; Zang X; Hsuan L; Waitz R; Locksley RM; Allen JE; Allison JP. 2005. Inducible costimulator is required for type 2 antibody isotype switching but not T helper cell type 2 responses in chronic nematode infection. Proc Natl Acad Sci U S A 102(28):9872-7. [PubMed: 15994233]  [MGI Ref ID J:99858]

Mahajan S; Cervera A; MacLeod M; Fillatreau S; Perona-Wright G; Meek S; Smith A; MacDonald A; Gray D. 2007. The role of ICOS in the development of CD4 T cell help and the reactivation of memory T cells. Eur J Immunol 37(7):1796-808. [PubMed: 17549732]  [MGI Ref ID J:123477]

Moore TV; Clay BS; Cannon JL; Histed A; Shilling RA; Sperling AI. 2011. Inducible costimulator controls migration of T cells to the lungs via down-regulation of CCR7 and CD62L. Am J Respir Cell Mol Biol 45(4):843-50. [PubMed: 21421907]  [MGI Ref ID J:190213]

Moore TV; Clay BS; Ferreira CM; Williams JW; Rogozinska M; Cannon JL; Shilling RA; Marzo AL; Sperling AI. 2011. Protective effector memory CD4 T cells depend on ICOS for survival. PLoS One 6(2):e16529. [PubMed: 21364749]  [MGI Ref ID J:171076]

Nurieva R; Thomas S; Nguyen T; Martin-Orozco N; Wang Y; Kaja MK; Yu XZ; Dong C. 2006. T-cell tolerance or function is determined by combinatorial costimulatory signals. EMBO J 25(11):2623-33. [PubMed: 16724117]  [MGI Ref ID J:109521]

Nurieva RI; Mai XM; Forbush K; Bevan MJ; Dong C. 2003. B7h is required for T cell activation, differentiation, and effector function. Proc Natl Acad Sci U S A 100(24):14163-8. [PubMed: 14615582]  [MGI Ref ID J:86697]

Odegard JM; DiPlacido LD; Greenwald L; Kashgarian M; Kono DH; Dong C; Flavell RA; Craft J. 2009. ICOS controls effector function but not trafficking receptor expression of kidney-infiltrating effector T cells in murine lupus. J Immunol 182(7):4076-84. [PubMed: 19299705]  [MGI Ref ID J:147130]

Odegard JM; Marks BR; DiPlacido LD; Poholek AC; Kono DH; Dong C; Flavell RA; Craft J. 2008. ICOS-dependent extrafollicular helper T cells elicit IgG production via IL-21 in systemic autoimmunity. J Exp Med 205(12):2873-86. [PubMed: 18981236]  [MGI Ref ID J:143221]

Park H; Li Z; Yang XO; Chang SH; Nurieva R; Wang YH; Wang Y; Hood L; Zhu Z; Tian Q; Dong C. 2005. A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17. Nat Immunol 6(11):1133-41. [PubMed: 16200068]  [MGI Ref ID J:112600]

Redpath SA; van der Werf N; Cervera AM; Macdonald AS; Gray D; Maizels RM; Taylor MD. 2013. ICOS controls Foxp3(+) regulatory T-cell expansion, maintenance and IL-10 production during helminth infection. Eur J Immunol 43(3):705-15. [PubMed: 23319295]  [MGI Ref ID J:193831]

Rojo JM; Pini E; Ojeda G; Bello R; Dong C; Flavell RA; Dianzani U; Portoles P. 2008. CD4+ICOS+ T lymphocytes inhibit T cell activation 'in vitro' and attenuate autoimmune encephalitis 'in vivo'. Int Immunol 20(4):577-89. [PubMed: 18310064]  [MGI Ref ID J:133495]

Shilling RA; Clay BS; Tesciuba AG; Berry EL; Lu T; Moore TV; Bandukwala HS; Tong J; Weinstock JV; Flavell RA; Horan T; Yoshinaga SK; Welcher AA; Cannon JL; Sperling AI. 2009. CD28 and ICOS play complementary non-overlapping roles in the development of Th2 immunity in vivo. Cell Immunol 259(2):177-84. [PubMed: 19646680]  [MGI Ref ID J:152804]

Tesciuba AG; Shilling RA; Agarwal MD; Bandukwala HS; Clay BS; Moore TV; Weinstock JV; Welcher AA; Sperling AI. 2008. ICOS costimulation expands Th2 immunity by augmenting migration of lymphocytes to draining lymph nodes. J Immunol 181(2):1019-24. [PubMed: 18606653]  [MGI Ref ID J:137473]

Vogel KU; Edelmann SL; Jeltsch KM; Bertossi A; Heger K; Heinz GA; Zoller J; Warth SC; Hoefig KP; Lohs C; Neff F; Kremmer E; Schick J; Repsilber D; Geerlof A; Blum H; Wurst W; Heikenwalder M; Schmidt-Supprian M; Heissmeyer V. 2013. Roquin Paralogs 1 and 2 Redundantly Repress the Icos and Ox40 Costimulator mRNAs and Control Follicular Helper T Cell Differentiation. Immunity 38(4):655-68. [PubMed: 23583643]  [MGI Ref ID J:196136]

Yu XZ; Liang Y; Nurieva RI; Guo F; Anasetti C; Dong C. 2006. Opposing effects of ICOS on graft-versus-host disease mediated by CD4 and CD8 T cells. J Immunol 176(12):7394-401. [PubMed: 16751384]  [MGI Ref ID J:132339]

Health & husbandry

The genotypes of the animals provided may not reflect those discussed in the strain description or the mating scheme utilized by The Jackson Laboratory prior to cryopreservation. Please inquire for possible genotypes for this specific strain.

Health & Colony Maintenance Information

Animal Health Reports

Production of mice from cryopreserved embryos or sperm occurs in a maximum barrier room, G200.

Colony Maintenance

Breeding & HusbandryWhen maintained as a live colony, homozygotes or heterozygotes may be bred.

Pricing and Purchasing

Pricing, Supply Level & Notes, Controls


Pricing for USA, Canada and Mexico shipping destinations View International Pricing

Cryopreserved

Cryopreserved Mice - Ready for Recovery

Price (US dollars $)
Cryorecovery* $2450.00
Animals Provided

At least two mice that carry the mutation (if it is a mutant strain) will be provided. Their genotypes may not reflect those discussed in the strain description. Please inquire for possible genotypes and see additional details below.

Standard Supply

Cryopreserved. Ready for recovery. Please refer to pricing and supply notes on the strain data sheet for further information.

Supply Notes

  • Cryorecovery - Standard.
    Progeny testing is not required.
    The average number of mice provided from recovery of our cryopreserved strains is 10. The total number of animals provided, their gender and genotype will vary. We will fulfill your order by providing at least two pair of mice, at least one animal of each pair carrying the mutation of interest. Please inquire if larger numbers of animals with specific genotype and genders are needed. Animals typically ship between 11 and 14 weeks from the date of your order. If a second cryorecovery is needed in order to provide the minimum number of animals, animals will ship within 25 weeks. IMPORTANT NOTE: The genotypes of animals provided may not reflect the mating scheme utilized by The Jackson Laboratory prior to cryopreservation, or that discussed in the strain description. Please inquire about possible genotypes which will be recovered for this specific strain. The Jackson Laboratory cannot guarantee the reproductive success of mice shipped to your facility. If the mice are lost after the first three days (post-arrival) or do not produce progeny at your facility, a new order and fee will be necessary.

    Cryorecovery to establish a Dedicated Supply for greater quantities of mice
    Mice recovered can be used to establish a dedicated colony to contractually supply you mice according to your requirements. Price by quotation. For more information on Dedicated Supply, please contact JAX® Services, Tel: 1-800-422-6423 (from U.S.A., Canada or Puerto Rico only) or 1-207-288-5845 (from any location).

Pricing for International shipping destinations View USA Canada and Mexico Pricing

Cryopreserved

Cryopreserved Mice - Ready for Recovery

Price (US dollars $)
Cryorecovery* $3185.00
Animals Provided

At least two mice that carry the mutation (if it is a mutant strain) will be provided. Their genotypes may not reflect those discussed in the strain description. Please inquire for possible genotypes and see additional details below.

Standard Supply

Cryopreserved. Ready for recovery. Please refer to pricing and supply notes on the strain data sheet for further information.

Supply Notes

  • Cryorecovery - Standard.
    Progeny testing is not required.
    The average number of mice provided from recovery of our cryopreserved strains is 10. The total number of animals provided, their gender and genotype will vary. We will fulfill your order by providing at least two pair of mice, at least one animal of each pair carrying the mutation of interest. Please inquire if larger numbers of animals with specific genotype and genders are needed. Animals typically ship between 11 and 14 weeks from the date of your order. If a second cryorecovery is needed in order to provide the minimum number of animals, animals will ship within 25 weeks. IMPORTANT NOTE: The genotypes of animals provided may not reflect the mating scheme utilized by The Jackson Laboratory prior to cryopreservation, or that discussed in the strain description. Please inquire about possible genotypes which will be recovered for this specific strain. The Jackson Laboratory cannot guarantee the reproductive success of mice shipped to your facility. If the mice are lost after the first three days (post-arrival) or do not produce progeny at your facility, a new order and fee will be necessary.

    Cryorecovery to establish a Dedicated Supply for greater quantities of mice
    Mice recovered can be used to establish a dedicated colony to contractually supply you mice according to your requirements. Price by quotation. For more information on Dedicated Supply, please contact JAX® Services, Tel: 1-800-422-6423 (from U.S.A., Canada or Puerto Rico only) or 1-207-288-5845 (from any location).

View USA Canada and Mexico Pricing View International Pricing

Standard Supply

Cryopreserved. Ready for recovery. Please refer to pricing and supply notes on the strain data sheet for further information.

Control Information

  Control
   001976 NOD/ShiLtJ
 
  Considerations for Choosing Controls
  Control Pricing Information for Genetically Engineered Mutant Strains.
 

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