Description

Strain Information

Type Mutant Stock; Targeted Mutation; Additional information on Genetically Engineered Mutant Mice. Species laboratory mouse Generation F?+11+N1p   Donating Investigator Timothy Ley,   Washington University School of Medicine

Appearance
white-bellied agouti
Related Genotype: A^w/?

black
Related Genotype: a/a

Description
Mice homozygous for the Gzmb^tm1Ley mutation are viable and fertile. Lymphopoiesis and peripheral lymphoid tissue development is normal. T cell responses to mitogenic (Con A and IL2) and allogeneic (mixed lymphocyte culture) stimulation are unaffected. There is a 10-fold reduction in condensation of chromatin resulting in nuclear crescents and pyknosis when Gzmb^tm1Ley CTL are used as effectors. Thus, activated CTL from homozygous mice are deficient in the early induction of DNA fragmentation and apoptosis in allogeneic target cells. Formerly called Ctla1.

Control Information

	Control
	101045 B6129SF2/J	(approximate)
Considerations for Choosing Controls

Related Strains

Strains carrying   Gzmb^tm1Ley allele

002248

B6.129S2-Gzmbtm1Ley/J

View Strains carrying   Gzmb^tm1Ley     (1 strain)

Phenotype

Phenotype Information

View Mammalian Phenotype Terms

Mammalian Phenotype Terms

      assigned by genotype

Gzmb^tm1Ley/Gzmb^tm1Ley

        involves: 129S2/SvPas * C57BL/6J

• immune system phenotype
• defective cytotoxic T cell cytolysis (MGI Ref ID J:23560)
  • cytotoxic T lymphocytes (CTLs) defective in ability to induce rapid DNA fragmentation and apoptosis in allogeneic target cells
  • with long incubation, fragmentation is partially and cell lysis completely rescued
  • normal activation and proliferation of cytotoxic T lymphocytes (CTLs) in mixed lymphocyte cultures (MLCs)

Gzmb^tm1Ley/Gzmb^tm1Ley

        involves: 129S2/SvPas * C57BL/6

• homeostasis/metabolism phenotype
• abnormal enzyme/coenzyme activity (MGI Ref ID J:113349)
  • specific activity of caspase 3 executioner protease in cytoplasm of CTLs is decreased

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

Gzmb^tm1Ley/Gzmb^tm1Ley

        B6.129S2-Gzmb^tm1Ley

• immune system phenotype
• impaired NK cell cytolysis (MGI Ref ID J:113213)
  • impaired ability of NK cells to induce DNA fragmenting but normal ability to induce membrane damage

View Research Applications

Research Applications

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

Gzmb^tm1Ley related

Apoptosis Research
Extracellular Modulators

Cancer Research
Growth Factors/Receptors/Cytokines

Immunology and Inflammation Research
Growth Factors/Receptors/Cytokines

Genes & Alleles

Gene & Allele Information

Allele Symbol		Gzmbtm1Ley
Allele Name		targeted mutation 1, Timothy J Ley
Allele Type		Targeted (knock-out)
Common Name(s)		GrB KO; Granzyme B-; GrzB-; Gzmb-/+PGK-neo; gzmB-;
Mutation Made By		Timothy Ley,   Washington University School of Medicine
Strain of Origin		129S2/SvPas
ES Cell Line Name		D3
ES Cell Line Strain		129S2/SvPas
Gene Symbol and Name		Gzmb, granzyme B
Chromosome		14
Gene Common Name(s)		AI553453; CCP-1/C11; CCP1; CCPI; CGL-1; CGL1; CSP-B; CSPB; CTLA1; CTSGL1; Ctla-1; Ctla1; HLP; MGC156565; SECT; cytotoxic T lymphocyte-associated protein 1; expressed sequence AI553453;
General Note		Homozygous mutant mice develop normally, with normal lymphopoiesis and hematopoiesis. However, CTLs from mutant mice are unable to induce rapid fragmentation of DNA and apoptosis in target cells; with long incubation, fragmentation is partially and cell lysis completely rescued (J:23560). Natural killer (NK) cells also release granzyme-bearing granules, and rapid cytoxicity by these cells is dependent on granzyme B. Granzyme B independent mechanisms of cytotoxicity exist, since CTLs from null homozygotescan lyse target cells after extended incubation, but these mechanism are not active in null mutant NK cells (J:28160).
Molecular Note		A PGK-neomycin resistance cassette replaced a 350bp AvrII fragment starting within the 5' untranslated region (22 bp upstream from the initiation codon), extending through exon 1 and part of intron 1. [MGI Ref ID J:23560]

Genotyping

Genotyping Information

Genotyping Protocols

Gzmb^tm1Ley, STD PCR, vers. 1

Helpful Links

Optimizing PCR Protocols

References

References

Selected Reference(s)

Heusel JW; Wesselschmidt RL; Shresta S; Russell JH; Ley TJ. 1994. Cytotoxic lymphocytes require granzyme B for the rapid induction of DNA fragmentation and apoptosis in allogeneic target cells. Cell 76(6):977-87. [PubMed: 8137431]  [MGI Ref ID J:23560]

Additional References

Gzmb^tm1Ley related

Alsharifi M; Lobigs M; Simon MM; Kersten A; Muller K; Koskinen A; Lee E; Mullbacher A. 2006. NK cell-mediated immunopathology during an acute viral infection of the CNS. Eur J Immunol 36(4):887-96. [PubMed: 16541469]  [MGI Ref ID J:114787]

Balkow S; Kersten A; Tran TT; Stehle T; Grosse P; Museteanu C; Utermohlen O; Pircher H; von Weizsacker F; Wallich R; Mullbacher A; Simon MM. 2001. Concerted action of the FasL/Fas and perforin/granzyme A and B pathways is mandatory for the development of early viral hepatitis but not for recovery from viral infection. J Virol 75(18):8781-91. [PubMed: 11507223]  [MGI Ref ID J:71217]

Cao X; Cai SF; Fehniger TA; Song J; Collins LI; Piwnica-Worms DR; Ley TJ. 2007. Granzyme B and perforin are important for regulatory T cell-mediated suppression of tumor clearance. Immunity 27(4):635-46. [PubMed: 17919943]  [MGI Ref ID J:126114]

Devadas S; Das J; Liu C; Zhang L; Roberts AI; Pan Z; Moore PA; Das G; Shi Y. 2006. Granzyme B is critical for T cell receptor-induced cell death of type 2 helper T cells. Immunity 25(2):237-47. [PubMed: 16901729]  [MGI Ref ID J:113469]

Einecke G; Fairhead T; Hidalgo LG; Sis B; Turner P; Zhu LF; Bleackley RC; Hadley GA; Famulski KS; Halloran PF. 2006. Tubulitis and epithelial cell alterations in mouse kidney transplant rejection are independent of CD103, perforin or granzymes A/B. Am J Transplant 6(9):2109-20. [PubMed: 16869802]  [MGI Ref ID J:135871]

Eisert V; Munster U; Simon MM; Moll H. 2002. The course of Leishmania major infection in mice lacking granzyme-mediated mechanisms. Immunobiology 205(3):314-20. [PubMed: 12182457]  [MGI Ref ID J:102819]

Fehniger TA; Cai SF; Cao X; Bredemeyer AJ; Presti RM; French AR; Ley TJ. 2007. Acquisition of murine NK cell cytotoxicity requires the translation of a pre-existing pool of granzyme B and perforin mRNAs. Immunity 26(6):798-811. [PubMed: 17540585]  [MGI Ref ID J:123588]

Goping IS; Sawchuk T; Rieger A; Shostak I; Bleackley RC. 2008. Cytotoxic T lymphocytes overcome Bcl-2 inhibition: target cells contribute to their own demise. Blood 111(4):2142-51. [PubMed: 18096765]  [MGI Ref ID J:131369]

Graubert TA; DiPersio JF; Russell JH; Ley TJ. 1997. Perforin/granzyme-dependent and independent mechanisms are both important for the development of graft-versus-host disease after murine bone marrow transplantation. J Clin Invest 100(4):904-11. [PubMed: 9259590]  [MGI Ref ID J:42355]

Halloran PF; Urmson J; Ramassar V; Melk A; Zhu LF; Halloran BP; Bleackley RC. 2004. Lesions of T-cell-mediated kidney allograft rejection in mice do not require perforin or granzymes A and B. Am J Transplant 4(5):705-12. [PubMed: 15084164]  [MGI Ref ID J:136768]

Licon Luna RM; Lee E; Mullbacher A; Blanden RV; Langman R; Lobigs M. 2002. Lack of both Fas ligand and perforin protects from flavivirus-mediated encephalitis in mice. J Virol 76(7):3202-11. [PubMed: 11884544]  [MGI Ref ID J:126472]

Martin SF; Dudda JC; Delattre V; Bachtanian E; Leicht C; Burger B; Weltzien HU; Simon JC. 2004. Fas-mediated inhibition of CD4+ T cell priming results in dominance of type 1 CD8+ T cells in the immune response to the contact sensitizer trinitrophenyl. J Immunol 173(5):3178-85. [PubMed: 15322178]  [MGI Ref ID J:92718]

Mullbacher A; Waring P; Tha Hla R; Tran T; Chin S; Stehle T; Museteanu C; Simon MM. 1999. Granzymes are the essential downstream effector molecules for the control of primary virus infections by cytolytic leukocytes. Proc Natl Acad Sci U S A 96(24):13950-5. [PubMed: 10570179]  [MGI Ref ID J:120037]

Muller U; Sobek V; Balkow S; Holscher C; Mullbacher A; Museteanu C; Mossmann H; Simon MM. 2003. Concerted action of perforin and granzymes is critical for the elimination of Trypanosoma cruzi from mouse tissues, but prevention of early host death is in addition dependent onthe FasL/Fas pathway. Eur J Immunol 33(1):70-8. [PubMed: 12594834]  [MGI Ref ID J:81397]

Pao LI; Sumaria N; Kelly JM; van Dommelen S; Cretney E; Wallace ME; Anthony DA; Uldrich AP; Godfrey DI; Papadimitriou JM; Mullbacher A; Degli-Esposti MA; Smyth MJ. 2005. Functional analysis of granzyme M and its role in immunity to infection. J Immunol 175(5):3235-43. [PubMed: 16116214]  [MGI Ref ID J:113213]

Pardo J; Balkow S; Anel A; Simon MM. 2002. The differential contribution of granzyme A and granzyme B in cytotoxic T lymphocyte-mediated apoptosis is determined by the quality of target cells. Eur J Immunol 32(7):1980-5. [PubMed: 12115618]  [MGI Ref ID J:115548]

Pham CT; MacIvor DM; Hug BA; Heusel JW; Ley TJ. 1996. Long-range disruption of gene expression by a selectable marker cassette. Proc Natl Acad Sci U S A 93(23):13090-5. [PubMed: 8917549]  [MGI Ref ID J:36637]

Phillips T; Opferman JT; Shah R; Liu N; Froelich CJ; Ashton-Rickardt PG. 2004. A role for the granzyme B inhibitor serine protease inhibitor 6 in CD8+ memory cell homeostasis. J Immunol 173(6):3801-9. [PubMed: 15356127]  [MGI Ref ID J:92766]

Revell PA; Grossman WJ; Thomas DA; Cao X; Behl R; Ratner JA; Lu ZH; Ley TJ. 2005. Granzyme B and the downstream granzymes C and/or F are important for cytotoxic lymphocyte functions. J Immunol 174(4):2124-31. [PubMed: 15699143]  [MGI Ref ID J:96538]

Riera L; Gariglio M; Pagano M; Gaiola O; Simon MM; Landolfo S. 2001. Control of murine cytomegalovirus replication in salivary glands during acute infection is independent of the Fas ligand/Fas system. New Microbiol 24(3):231-8. [PubMed: 11497079]  [MGI Ref ID J:109866]

Riera L; Gariglio M; Valente G; Mullbacher A; Museteanu C; Landolfo S; Simon MM. 2000. Murine cytomegalovirus replication in salivary glands is controlled by both perforin and granzymes during acute infection. Eur J Immunol 30(5):1350-5. [PubMed: 10820381]  [MGI Ref ID J:62197]

Shresta S; Graubert TA; Thomas DA; Raptis SZ; Ley TJ. 1999. Granzyme A initiates an alternative pathway for granule-mediated apoptosis. Immunity 10(5):595-605. [PubMed: 10367905]  [MGI Ref ID J:55398]

Shresta S; Heusel JW; Macivor DM; Wesselschmidt RL; Russell JH; Ley TJ. 1995. Granzyme B plays a critical role in cytotoxic lymphocyte-induced apoptosis. Immunol Rev 146:211-21. [PubMed: 7493755]  [MGI Ref ID J:28160]

Simon MM; Hausmann M; Tran T; Ebnet K; Tschopp J; ThaHla R; Mullbacher A. 1997. In vitro- and ex vivo-derived cytolytic leukocytes from granzyme A x B double knockout mice are defective in granule-mediated apoptosis but not lysis of target cells. J Exp Med 186(10):1781-6. [PubMed: 9362539]  [MGI Ref ID J:44204]

Sipione S; Ewen C; Shostak I; Michalak M; Bleackley RC. 2005. Impaired cytolytic activity in calreticulin-deficient CTLs. J Immunol 174(6):3212-9. [PubMed: 15749851]  [MGI Ref ID J:97687]

Smyth MJ; Street SE; Trapani JA. 2003. Cutting edge: granzymes A and B are not essential for perforin-mediated tumor rejection. J Immunol 171(2):515-8. [PubMed: 12847210]  [MGI Ref ID J:123462]

Sutton VR; Waterhouse NJ; Browne KA; Sedelies K; Ciccone A; Anthony D; Koskinen A; Mullbacher A; Trapani JA. 2007. Residual active granzyme B in cathepsin C-null lymphocytes is sufficient for perforin-dependent target cell apoptosis. J Cell Biol 176(4):425-33. [PubMed: 17283185]  [MGI Ref ID J:119725]

Wang Y; Lobigs M; Lee E; Mullbacher A. 2004. Exocytosis and Fas mediated cytolytic mechanisms exert protection from West Nile virus induced encephalitis in mice. Immunol Cell Biol 82(2):170-3. [PubMed: 15061770]  [MGI Ref ID J:90852]

Waring P; Mullbacher A. 2001. Cell death mediated by alloreactive cytotoxic T cells via the granule exocytosis or the Fas pathway is independent of p34cdc2 kinase: Fas dependent killing of cells arrested in the cell cycle. Immunol Cell Biol 79(3):264-73. [PubMed: 11380680]  [MGI Ref ID J:110426]

Waterhouse NJ; Sutton VR; Sedelies KA; Ciccone A; Jenkins M; Turner SJ; Bird PI; Trapani JA. 2006. Cytotoxic T lymphocyte-induced killing in the absence of granzymes A and B is unique and distinct from both apoptosis and perforin-dependent lysis. J Cell Biol 173(1):133-44. [PubMed: 16606695]  [MGI Ref ID J:107828]

Zelinskyy G; Balkow S; Schimmer S; Schepers K; Simon MM; Dittmer U. 2004. Independent roles of perforin, granzymes, and Fas in the control of Friend retrovirus infection. Virology 330(2):365-74. [PubMed: 15567431]  [MGI Ref ID J:95485]

Zhang M; Park SM; Wang Y; Shah R; Liu N; Murmann AE; Wang CR; Peter ME; Ashton-Rickardt PG. 2006. Serine protease inhibitor 6 protects cytotoxic T cells from self-inflicted injury by ensuring the integrity of cytotoxic granules. Immunity 24(4):451-61. [PubMed: 16618603]  [MGI Ref ID J:113349]

van Dommelen SL; Sumaria N; Schreiber RD; Scalzo AA; Smyth MJ; Degli-Esposti MA. 2006. Perforin and granzymes have distinct roles in defensive immunity and immunopathology. Immunity 25(5):835-48. [PubMed: 17088087]  [MGI Ref ID J:116116]

Health & husbandry

Health & Colony Maintenance Information

Colony Maintenance

Diet Information	LabDiet® 5K52/5K67

Purchasing information

Pricing, Supply Level & Notes, Controls, General Terms & Conditions

Pricing

Supply Details

Standard Supply

Repository-Cryopreserved. Must Be Recovered. Please refer to pricing and supply notes for further information.

Supply Notes

Cryorecovery - Standard. The recovery process begins when a signed agreement form is returned to the Customer Service Department after order placement. Although results vary by strain, at least two males and two females (two pairs) will be provided, typically within 15 weeks of our receipt of the signed agreement form. If the first recovery attempt is unsuccessful or only one pair is recovered, a second recovery will be done, extending the delivery time to approximately 25 weeks. At least one member of each pair will be of known genotype and will carry the mutation if it is a mutant strain. Please note that pairs may not reflect the mating scheme utilized by The Jackson Laboratory prior to cryopreservation of the strain. Mating schemes are sometimes modified for successful cryopreservation. Price represents a repository maintenance fee, which includes the cost of recovery of the strain from the cryopreservation resource and the periodic replacement of the frozen embryos used for recovery. Cryorecovery to establish a Dedicated Supply for greater quantities of mice. One to two pairs will be recovered to establish a Dedicated Supply of mice. Price by quotation. For more information on Dedicated Supply, please contact JAX® Services, Tel: 1-800-422-6423 or 1-207-288-5845. This strain is included in the Induced Mutant Resource Colony collection. Genomic DNA is available for this strain from the Mouse DNA Resource.

Control Information

	Control
	101045 B6129SF2/J	(approximate)
Considerations for Choosing Controls
USA, Canada and Mexico - Control Pricing Information for Genetically Engineered Mutant Strains.
International - Control Pricing Information for Genetically Engineered Mutant Strains.

General Terms and Conditions

See Terms of Use

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 and Purchasing Information

      Purchasing Information
      JAX^® Mice Orders
      Surgical Services

Contact Information
Orders & Technical Support
Tel: 800.422.6423 or 207.288.5845
Fax: 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 & Services Conditions of Use

“Each recipient institution, including its employees and other researchers under its control (RECIPIENT), of mice or services using mice from The Jackson Laboratory (TJL) agrees that such mice, descendants of those mice derived by inbreeding or crossbreeding, including unmodified derivatives of those mice or their descendants (“MICE”) shall not be: (i) used for any purpose other than the internal research of the RECIPIENT, (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 with respect to MICE. Acceptance of MICE from TJL shall be deemed agreement by RECIPIENT to these conditions, and departure from these conditions requires The Jackson Laboratory’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, The Jackson Laboratory will, at its option, provide credit or replacement for the MICE or product received or the services provided.

No Liability

In no event shall The Jackson Laboratory, 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 The Jackson Laboratory, its agents or employees. In purchasing or receiving MICE, products or services from The Jackson Laboratory, purchaser or recipient, or any party claiming by or through them, expressly releases and discharges The Jackson Laboratory from all such causes of action or damages, and further agrees to defend and indemnify The Jackson Laboratory from any costs or damages arising out of any third party claims.

MICE and biological materials 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 The Jackson Laboratory’s MICE, products and services. In addition, special terms and conditions of sale of certain MICE, products and services may be set forth separately in The Jackson Laboratory 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 The Jackson Laboratory, 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 The Jackson Laboratory, 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 services by The Jackson Laboratory.