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

Type Congenic; Mutant Strain; Targeted Mutation; Additional information on Genetically Engineered and Mutant Mice. Visit our online Nomenclature tutorial. Additional information on Congenic nomenclature. Species laboratory mouse Background Strain NOD/ShiLtJ Donor Strain 129 (R1 ES cells) H2 Haplotype g7 Generation ?+N1p (08-MAY-05) Generation Definitions   Donating Investigator Christophe Benoist,   Joslin Diabetes Center

Appearance
pink-eyed abino
Related Genotype: A/? Tyr^c/Tyr^c

Description
Heterozygous Ctla4^tm1All mice are viable, fertile, and normal in size and exhibit diabetes incidence comparable to NOD.

Ctla4^tm1All homozygous mice on various backgrounds, including C57BL/6, BALB/c, 129 and NOD, die at 3-4 weeks of age due to massive polyclonal expansion of T-cells and massive lymphocyte infiltration into non-lymphoid organs, such as heart, liver, lung and pancreas. Treatment with murine Ctla4Ig or depletion of CD4⁺ T-cells blocks this lymphoproliferative disease. Splenic and lymph node T-cells display an activated phenotype characterized as CD69⁺, CD25⁺, CD44^hi, Mel14^lo, CD45RB^lo and Sca1^hi and have down regulated the TCR. Lymph node and spleen cells cultured from Ctla4^tm1All homozygous mice spontaneously proliferate while wild-type controls do not. Cells from whole lymph nodes or purified T-cells are unresponsive to anti CD28mAb stimulation, while rIl2 increases the proliferative response. Homozygous Ctla4^tm1All NOD mice also transgenically expressing the BDC2.5 alpha and beta TCR chains do not exhibit the lymphoproliferative phenotype. Other TCR transgenes exert a similar effect on differing backgrounds. However, all of the mice develop aggressive autoimmunity and rapidly develop diabetes by7 weeks of age.In contrast, mice heterozygous for Ctla4^tm1All and transgenically expressing the BDC2.5 TCR have late and relatively rare diabetes.

NOD.129(B6)-Ctla4^tm1All/DoiJ may be useful for studying the role of Ctla4/Cd28:Cd80/Cd86 in the regulation of self tolerance and susceptibility to autoimmune diseases.

Development
A construct containing a neomycin expression cassette inserted into exon 3 of Ctla4 (cloned from 129/Sv mouse) was transfected into R1 ((129X1/SvJ x 129S1/Sv)F1-Kitl +) embryonic stem cells (ES cells). These ES cells were injected into C57BL/6 blastocysts. To establish a colony and germ line transmission chimeric mice were backcrossed to C57BL/6 (Chambers et, al, 1997). Luhder et al. 2000, subsequently backcrossed this mutation to NOD/LtJ. In 2004, the Type 1 Diabetes Resource received NOD.129(B6)- Ctla4^tm1All /DoiJ heterozygotes at generation N18.

Control Information

	Control
	Wild-type from the colony
	001976 NOD/ShiLtJ
Considerations for Choosing Controls

Related Strains

Strains carrying other alleles of Ctla4

002980

C57BL/6-Tg(Cd152Ig)1Jbs/J

View Strains carrying other alleles of Ctla4     (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.

Ctla4^tm1All/Ctla4^tm1All

        involves: 129S1/Sv * 129X1/SvJ * C57BL/6 * NOD

• mortality/aging
• premature death
  • mice die at 3 to 4 weeks of age   (MGI Ref ID J:109887)
• immune system phenotype
• increased acute inflammation
  • at 3 weeks, mice exhibit extensive infiltration of the heart, liver, and pancreas unlike in wild-type mice   (MGI Ref ID J:109887)

View Research Applications

Research Applications

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

Ctla4^tm1All related

Cancer Research
Growth Factors/Receptors/Cytokines

Diabetes and Obesity Research
Type 1 Diabetes (IDDM) Analysis Strains
      NOD Congenics with Mutations Affecting Cytokine Production by Autoreactive T Cells

Immunology and Inflammation Research
CD Antigens, Antigen Receptors, and Histocompatibility Markers
Growth Factors/Receptors/Cytokines

Genes & Alleles

Gene & Allele Information provided by MGI

Allele Symbol		Ctla4tm1All
Allele Name		targeted mutation 1, James P Allison
Allele Type		Targeted (knock-out)
Common Name(s)		CTLA-4 KO; CTLA-4-; Ctla4o; Ctla4o;
Strain of Origin		(129X1/SvJ x 129S1/Sv)F1-Kitl<+>
ES Cell Line Name		R1
ES Cell Line Strain		(129X1/SvJ x 129S1/Sv)F1-Kitl<+>
Gene Symbol and Name		Ctla4, cytotoxic T-lymphocyte-associated protein 4
Chromosome		1
Gene Common Name(s)		CD; CD152; CD152 antigen; CELIAC3; CTLA-4; Cd152; Ctla-4; GRD4; GSE; ICOS; IDDM12; Ly-56; cytotoxic T lymphocyte-associated protein 4; sCTLA4;
Molecular Note		The insertion of neomycin selection cassette under the control of a PGK promoter disrupted exon 3. [MGI Ref ID J:42481]

Genotyping

Genotyping Information

Genotyping Protocols

Ctla4^tm1All, Standard PCR

Helpful Links

Genotyping resources and troubleshooting

References

References provided by MGI

Selected Reference(s)

Luhder F; Chambers C; Allison JP; Benoist C; Mathis D. 2000. Pinpointing when T cell costimulatory receptor CTLA-4 must be engaged to dampen diabetogenic T cells. Proc Natl Acad Sci U S A 97(22):12204-9. [PubMed: 11035773]  [MGI Ref ID J:109887]

Additional References

Chambers CA; Cado D; Truong T; Allison JP. 1997. Thymocyte development is normal in CTLA-4-deficient mice. Proc Natl Acad Sci U S A 94(17):9296-301. [PubMed: 9256476]  [MGI Ref ID J:42481]

Tivol EA; Borriello F; Schweitzer AN; Lynch WP; Bluestone JA; Sharpe AH. 1995. Loss of CTLA-4 leads to massive lymphoproliferation and fatal multiorgan tissue destruction, revealing a critical negative regulatory role of CTLA-4. Immunity 3(5):541-7. [PubMed: 7584144]  [MGI Ref ID J:30393]

Waterhouse P; Bachmann MF; Penninger JM; Ohashi PS; Mak TW. 1997. Normal thymic selection, normal viability and decreased lymphoproliferation in T cell receptor-transgenic CTLA-4-deficient mice. Eur J Immunol 27(8):1887-92. [PubMed: 9295023]  [MGI Ref ID J:42659]

Ctla4^tm1All related

Chambers CA; Cado D; Truong T; Allison JP. 1997. Thymocyte development is normal in CTLA-4-deficient mice. Proc Natl Acad Sci U S A 94(17):9296-301. [PubMed: 9256476]  [MGI Ref ID J:42481]

Chambers CA; Kang J; Wu Y; Held W; Raulet DH; Allison JP. 2002. The lymphoproliferative defect in CTLA-4-deficient mice is ameliorated by an inhibitory NK cell receptor. Blood 99(12):4509-16. [PubMed: 12036882]  [MGI Ref ID J:77052]

Chambers CA; Kuhns MS; Allison JP. 1999. Cytotoxic T lymphocyte antigen-4 (CTLA-4) regulates primary and secondary peptide-specific CD4(+) T cell responses. Proc Natl Acad Sci U S A 96(15):8603-8. [PubMed: 10411922]  [MGI Ref ID J:119845]

Chambers CA; Sullivan TJ; Allison JP. 1997. Lymphoproliferation in CTLA-4-deficient mice is mediated by costimulation-dependent activation of CD4+ T cells. Immunity 7(6):885-95. [PubMed: 9430233]  [MGI Ref ID J:111523]

Chambers CA; Sullivan TJ; Truong T; Allison JP. 1998. Secondary but not primary T cell responses are enhanced in CTLA-4-deficient CD8+ T cells. Eur J Immunol 28(10):3137-43. [PubMed: 9808182]  [MGI Ref ID J:114212]

Chen Z; Stockton J; Mathis D; Benoist C. 2006. Modeling CTLA4-linked autoimmunity with RNA interference in mice. Proc Natl Acad Sci U S A 103(44):16400-5. [PubMed: 17060611]  [MGI Ref ID J:115599]

Gattinoni L; Ranganathan A; Surman DR; Palmer DC; Antony PA; Theoret MR; Heimann DM; Rosenberg SA; Restifo NP. 2006. CTLA-4 dysregulation of self/tumor-reactive CD8+ T-cell function is CD4+ T-cell dependent. Blood 108(12):3818-23. [PubMed: 16882704]  [MGI Ref ID J:140448]

Hegel JK; Knieke K; Kolar P; Reiner SL; Brunner-Weinzierl MC. 2009. CD152 (CTLA-4) regulates effector functions of CD8+ T lymphocytes by repressing Eomesodermin. Eur J Immunol 39(3):883-93. [PubMed: 19224637]  [MGI Ref ID J:146787]

Hoff H; Kolar P; Ambach A; Radbruch A; Brunner-Weinzierl MC. 2010. CTLA-4 (CD152) inhibits T cell function by activating the ubiquitin ligase Itch. Mol Immunol 47(10):1875-81. [PubMed: 20417562]  [MGI Ref ID J:160620]

Inobe M; Schwartz RH. 2004. CTLA-4 engagement acts as a brake on CD4+ T cell proliferation and cytokine production but is not required for tuning T cell reactivity in adaptive tolerance. J Immunol 173(12):7239-48. [PubMed: 15585846]  [MGI Ref ID J:94863]

Ise W; Kohyama M; Nutsch KM; Lee HM; Suri A; Unanue ER; Murphy TL; Murphy KM. 2010. CTLA-4 suppresses the pathogenicity of self antigen-specific T cells by cell-intrinsic and cell-extrinsic mechanisms. Nat Immunol 11(2):129-35. [PubMed: 20037585]  [MGI Ref ID J:158400]

Khattri R; Cox T; Yasayko SA; Ramsdell F. 2003. An essential role for Scurfin in CD4+CD25+ T regulatory cells. Nat Immunol 4(4):337-42. [PubMed: 12612581]  [MGI Ref ID J:128566]

Pandiyan P; Gartner D; Soezeri O; Radbruch A; Schulze-Osthoff K; Brunner-Weinzierl MC. 2004. CD152 (CTLA-4) determines the unequal resistance of Th1 and Th2 cells against activation-induced cell death by a mechanism requiring PI3 kinase function. J Exp Med 199(6):831-42. [PubMed: 15007096]  [MGI Ref ID J:90481]

Pandiyan P; Hegel JK; Krueger M; Quandt D; Brunner-Weinzierl MC. 2007. High IFN-gamma production of individual CD8 T lymphocytes is controlled by CD152 (CTLA-4). J Immunol 178(4):2132-40. [PubMed: 17277117]  [MGI Ref ID J:143993]

Pedicord VA; Montalvo W; Leiner IM; Allison JP. 2011. Single dose of anti-CTLA-4 enhances CD8+ T-cell memory formation, function, and maintenance. Proc Natl Acad Sci U S A 108(1):266-71. [PubMed: 21173239]  [MGI Ref ID J:169010]

Peggs KS; Quezada SA; Chambers CA; Korman AJ; Allison JP. 2009. Blockade of CTLA-4 on both effector and regulatory T cell compartments contributes to the antitumor activity of anti-CTLA-4 antibodies. J Exp Med 206(8):1717-25. [PubMed: 19581407]  [MGI Ref ID J:151491]

Quandt D; Hoff H; Rudolph M; Fillatreau S; Brunner-Weinzierl MC. 2007. A new role of CTLA-4 on B cells in thymus-dependent immune responses in vivo. J Immunol 179(11):7316-24. [PubMed: 18025174]  [MGI Ref ID J:154822]

Rudolph M; Hebel K; Miyamura Y; Maverakis E; Brunner-Weinzierl MC. 2011. Blockade of CTLA-4 decreases the generation of multifunctional memory CD4+ T cells in vivo. J Immunol 186(10):5580-9. [PubMed: 21478403]  [MGI Ref ID J:173092]

Sojka DK; Hughson A; Fowell DJ. 2009. CTLA-4 is required by CD4+CD25+ Treg to control CD4+ T-cell lymphopenia-induced proliferation. Eur J Immunol 39(6):1544-51. [PubMed: 19462377]  [MGI Ref ID J:149528]

Stohl W; Jacob N; Quinn WJ 3rd; Cancro MP; Gao H; Putterman C; Gao X; Pricop L; Koss MN. 2008. Global T cell dysregulation in non-autoimmune-prone mice promotes rapid development of BAFF-independent, systemic lupus erythematosus-like autoimmunity. J Immunol 181(1):833-41. [PubMed: 18566449]  [MGI Ref ID J:137391]

Stohl W; Xu D; Kim KS; David CS; Allison JP. 2004. MHC class II-independent and -dependent T cell expansion and B cell hyperactivity in vivo in mice deficient in CD152 (CTLA-4). Int Immunol 16(7):895-904. [PubMed: 15136557]  [MGI Ref ID J:90671]

Sugita S; Futagami Y; Horie S; Mochizuki M. 2007. Transforming growth factor beta-producing Foxp3(+)CD8(+)CD25(+) T cells induced by iris pigment epithelial cells display regulatory phenotype and acquire regulatory functions. Exp Eye Res 85(5):626-36. [PubMed: 17720157]  [MGI Ref ID J:132325]

Sugita S; Keino H; Futagami Y; Takase H; Mochizuki M; Stein-Streilein J; Streilein JW. 2006. B7+ iris pigment epithelial cells convert T cells into CTLA-4+, B7-expressing CD8+ regulatory T cells. Invest Ophthalmol Vis Sci 47(12):5376-84. [PubMed: 17122127]  [MGI Ref ID J:123098]

Sugita S; Ng TF; Lucas PJ; Gress RE; Streilein JW. 2006. B7+ iris pigment epithelium induce CD8+ T regulatory cells; both suppress CTLA-4+ T cells. J Immunol 176(1):118-27. [PubMed: 16365402]  [MGI Ref ID J:126250]

Sugita S; Ng TF; Schwartzkopff J; Streilein JW. 2004. CTLA-4+CD8+ T cells that encounter B7-2+ iris pigment epithelial cells express their own B7-2 to achieve global suppression of T cell activation. J Immunol 172(7):4184-94. [PubMed: 15034031]  [MGI Ref ID J:88713]

Sugita S; Streilein JW. 2003. Iris pigment epithelium expressing CD86 (B7-2) directly suppresses T cell activation in vitro via binding to cytotoxic T lymphocyte-associated antigen 4. J Exp Med 198(1):161-71. [PubMed: 12835481]  [MGI Ref ID J:84466]

Sullivan TJ; Letterio JJ; van Elsas A; Mamura M; van Amelsfort J; Sharpe S; Metzler B; Chambers CA; Allison JP. 2001. Lack of a role for transforming growth factor-beta in cytotoxic T lymphocyte antigen-4-mediated inhibition of T cell activation. Proc Natl Acad Sci U S A 98(5):2587-92. [PubMed: 11226283]  [MGI Ref ID J:135466]

Winstead CJ; Reilly CS; Moon JJ; Jenkins MK; Hamilton SE; Jameson SC; Way SS; Khoruts A. 2010. CD4(+)CD25(+)Foxp3(+) regulatory T cells optimize diversity of the conventional T cell repertoire during reconstitution from lymphopenia. J Immunol 184(9):4749-60. [PubMed: 20357265]  [MGI Ref ID J:160453]

Zheng SG; Wang JH; Stohl W; Kim KS; Gray JD; Horwitz DA. 2006. TGF-beta requires CTLA-4 early after T cell activation to induce FoxP3 and generate adaptive CD4+CD25+ regulatory cells. J Immunol 176(6):3321-9. [PubMed: 16517699]  [MGI Ref ID J:129539]

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, RG10/RG30.

Colony Maintenance

Breeding & Husbandry	Homozygotes die at 3-4 weeks of age. Heterozygotes become diabetic similar to NOD/LtJ. A footpad injection of Complete Freund s Adjuvant (CFA) administered once at weaning will delay diabetes onset, thus extending the lifespan of breeders. Use of Complete Freund s Adjuvant in NOD mice can be found in Current Protocols in Immunology page 15.9.19, Reproduction.
Diet Information	LabDiet® 5K52/5K67

Purchasing information

Pricing, Supply Level & Notes, Controls

General Supply Notes

• This strain is included in the Type 1 Diabetes Repository collection.
• Genomic DNA is available for this strain from the Mouse DNA Resource.

Control Information

	Control
	Wild-type from the colony
	001976 NOD/ShiLtJ
Considerations for Choosing Controls
Control Pricing Information for Genetically Engineered Mutant Strains.

Payment Terms and Conditions

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.

---

Ordering Information
JAX^® Mice
Surgical and Preconditioning Services
JAX^® Services
Customer Services and Support
Tel: 1-800-422-6423 or 1-207-288-5845
Fax: 1-207-288-6150
Technical Support Email Form

Terms of Use

Terms of Use

General Terms and Conditions

Contact information

General inquiries

Contracts Administration

phone:	207-288-6470
fax:	207-288-6655

JAX^® Mice, Products & Services Conditions of Use

"MICE" means mouse strains, their progeny derived by inbreeding or crossbreeding, unmodified derivatives from mouse strains or their progeny supplied by The Jackson Laboratory ("JACKSON"). "PRODUCTS" means biological materials supplied by JACKSON, and their derivatives. "RECIPIENT" means each recipient of MICE, PRODUCTS, or services provided by JACKSON including each institution, its employees and other researchers under its control. MICE or PRODUCTS shall not be: (i) used for any purpose other than the internal research, (ii) sold or otherwise provided to any third party for any use, or (iii) provided to any agent or other third party to provide breeding or other services. Acceptance of MICE or PRODUCTS from JACKSON shall be deemed as agreement by RECIPIENT to these conditions, and departure from these conditions requires JACKSON's prior written authorization.

In case of dissatisfaction for a valid reason and claimed in writing by a purchaser within ninety (90) days of receipt of mice, products or services, JACKSON will, at its option, provide credit or replacement for the mice or product received or the services provided.

No Liability

In no event shall JACKSON, its trustees, directors, officers, employees, and affiliates be liable for any causes of action or damages, including any direct, indirect, special, or consequential damages, arising out of the provision of MICE, PRODUCTS or services, including economic damage or injury to property and lost profits, and including any damage arising from acts or negligence on the part of JACKSON, its agents or employees. Unless prohibited by law, in purchasing or receiving MICE, PRODUCTS or services from JACKSON, purchaser or recipient, or any party claiming by or through them, expressly releases and discharges JACKSON from all such causes of action or damages, and further agrees to defend and indemnify JACKSON from any costs or damages arising out of any third party claims.

MICE and PRODUCTS are to be used in a safe manner and in accordance with all applicable governmental rules and regulations.

The foregoing represents the General Terms and Conditions applicable to JACKSON’s MICE, PRODUCTS or services. In addition, special terms and conditions of sale of certain MICE, PRODUCTS or services may be set forth separately in JACKSON web pages, catalogs, price lists, contracts, and/or other documents, and these special terms and conditions shall also govern the sale of these MICE, PRODUCTS and services by JACKSON, and by its licensees and distributors.

Acceptance of delivery of MICE, PRODUCTS or services shall be deemed agreement to these terms and conditions. No purchase order or other document transmitted by purchaser or recipient that may modify the terms and conditions hereof, shall be in any way binding on JACKSON, and instead the terms and conditions set forth herein, including any special terms and conditions set forth separately, shall govern the sale of MICE, PRODUCTS or services by JACKSON.