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Information on EC 3.4.21.78 - granzyme A and Organism(s) Mus musculus and UniProt Accession P11032
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3.4.21.78 granzyme ASpecify your search results
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- 3.4.21.78
- thrombospondin-1
- angiogenesis
- endothelial
- perforin
-
killer
- granule
-
angiogenic
-
antiangiogenic
-
cytolytic
-
matricellular
- metastasis
- collagen
-
microvessels
- t-cells
-
microvascular
- integrins
- fibrosis
- fibronectin
- cd8
- tgf-beta1
- neovascularization
- fasl
- fgf-2
-
corneal
- alphavbeta3
-
exocytosis
-
ctl-mediated
- factor-beta
- bfgf
- medicine
-
caspase-independent
-
angiogenesis-related
-
granule-associated
-
integrin-associated
-
angiostatic
-
proangiogenic
-
metronomic
- properdin
- endostatin
-
granulysin
-
tregs
-
lymphocyte-mediated
-
lymphokine-activated
- ifn-gamma
- vegf-a
The taxonomic range for the selected organisms is: Mus musculus
The enzyme appears in selected viruses and cellular organisms
The enzyme appears in selected viruses and cellular organisms
Synonyms
tsp-1, granzyme a, h factor, gzm a, gzma/k, ctla3, ctl tryptase, 
more
topSYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
Autocrine thymic lymphoma granzyme-like serine protease
-
-
-
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CTL tryptase
-
-
-
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CTLA3
-
-
-
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Cytotoxic T lymphocyte serine protease
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-
-
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H factor
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-
-
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Hanukkah factor
-
-
-
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HuTPS
-
-
-
-
T-cell associated protease 1
-
-
-
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T-cell derived serine proteinase 1
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-
-
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TSP-1
-
-
-
-
REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
hydrolysis of peptide bond
-
-
-
-
CAS REGISTRY NUMBER
COMMENTARY
143180-73-8
-
SUBSTRATE
PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide + H2O
?
MTT, benzyloxy-carbonyl-Lys-thiobenzyl ester, standard MTT-assay measuring loss of mitochondrial respiration, interspecies differences of granzyme A between human and mouse analyzed, mouse granzyme A is considerably more cytotoxic than human granzyme A
-
-
?
H-D-Pro-Phe-Arg p-nitroanilide + H2O
H-D-Pro-Phe-Arg + p-nitroaniline
i.e. S2302, measurement of enzymatic activity of granzyme A activity in lysates of CD8+ TAL
-
-
?
N-acetyl-Ile-Glu-Pro-Asp p-nitroanilide + H2O
N-acetyl-Ile-Glu-Pro-Asp + p-nitroaniline
measurement of enzymatic activity of granzyme A activity in lysates of CD8+ TAL
-
-
?
Abz-GLFRSLSS(K-dnp)D + H2O
Abz-GLFR + SLSS(K-dnp)D
-
a quenched fluorescence peptide substrate
-
-
?
Abz-VANRSAS(Kdnp)D + H2O
Abz-VANR + SAS(Kdnp)D
-
a quenched fluorescence peptide substrate
-
-
?
benzyloxycarbonyl-Gly-Arg thiobenzyl ester + H2O
benzyloxycarbonyl-Gly-Arg + phenylmethanethiol
-
-
-
-
?
benzyloxycarbonyl-Lys-thiobenzyl ester + H2O
benzyloxycarbonyl-Lys + phenylmethanethiol
-
-
-
-
?
D-Pro-Phe-Arg 4-nitroanilide + H2O
D-Pro-Phe-Arg + 4-nitroaniline
-
low or no activity against peptide synthetic substrates carrying other amino acid sequences at position P2, P3 adjacent to L-arginine or against substrates in which amino acids other than L-arginine are bound to the nitroanilide group
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?
additional information
?
-
-
TSP-1 has the capacity to stimulate B lymphocytes for proliferation in the absence of antigen
-
-
?
additional information
?
-
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overview: possible roles of granzyme A: 1. involvement in T or NK cell-mediated cytolysis, 2. in extravasation of T-lymphocytes, 3. in regulation of B cell growth, 4. in control of viral infection
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-
?
additional information
?
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-
by cleaving a variety of basement membrane-associated substrates, granzyme A may disintegrate the supramolecular structure of subendothelial basement membranes in a way that allows a more rapid emigration of activated T-cells
-
-
?
additional information
?
-
-
substrate specificity, comparison to the human enzyme at the peptide and proteome-wide levels, overview
-
-
?
NATURAL SUBSTRATE
NATURAL PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
additional information
?
-
-
TSP-1 has the capacity to stimulate B lymphocytes for proliferation in the absence of antigen
-
-
?
additional information
?
-
-
overview: possible roles of granzyme A: 1. involvement in T or NK cell-mediated cytolysis, 2. in extravasation of T-lymphocytes, 3. in regulation of B cell growth, 4. in control of viral infection
-
-
?
additional information
?
-
-
by cleaving a variety of basement membrane-associated substrates, granzyme A may disintegrate the supramolecular structure of subendothelial basement membranes in a way that allows a more rapid emigration of activated T-cells
-
-
?
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
Isocoumarins
-
mechanism-based isocoumarin inhibitors substituted with basic guanidino or isothiureidopropoxy groups
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Serpinb6b
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potent inhibitor, Serpinb6b employs an exosite to specifically inhibit dimeric but not monomeric murine enzyme. Kinetic analysis and modeling of the mGzmA-Serpinb6b Michaelis complex, overview
-
additional information
-
not: inhibitors of either thiol-, metallo- or carboxyl-proteinases
-
additional information
-
substrate specificity-based screening for potential inhibitors from the intracellular serpin family, overview. A lineage-specific increase in enzyme cytotoxic potential has driven cognate inhibitor evolution
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KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
TURNOVER NUMBER [1/s]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
SPECIFIC ACTIVITY [µmol/min/mg]
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
additional information
additional information
ability of human and mouse granzyme A to kill human or mouse cells in the presence of perforin analyzed, recombinant and native proteins tested, cytotoxic potential between mouse and human granzyme A different, mouse but not human granzyme A induces perforin-dependent cell death
additional information
-
ability of human and mouse granzyme A to kill human or mouse cells in the presence of perforin analyzed, recombinant and native proteins tested, cytotoxic potential between mouse and human granzyme A different, mouse but not human granzyme A induces perforin-dependent cell death
additional information
enzymatic activity of granzyme A measured in lysates of CD8+ tumor associated lymphocytes of interleukin 4-deficient and wild-type BALB/c mice, significant increase in the fraction of CD8+ tumor associated T-cells expressing granzyme A identified, in interleukin 4-deficient mice, the frequency of CD8+ tumor associated lymphocytes expressing granzyme A significantly increases between days 8 and 14, expression at background levels by day 21, increase in the percentage of CD8+ tumor associated lymphocytes expressing granzyme A less pronounced in wild-type mice
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
granzyme A precursor; interleukin 4-deficient BALB/c mice and wild-type BALB/c controls
SwissProt
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SOURCE
lysates of CD8+ tumor associated lymphocytes, Interleukin 4-deficient mice
additional information
GZMA is expressed in lungs from wild-type and Mycobacterium tuberculosis-infected mice
regulatory T cells (Tregs), CD4+ T-cells and CD4+CD25- T-cells from wild-type and gzmA-/- mice
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cee lysates, activated, including normal peripheral blood lymphocytes previously sensitized by interleukin 2 or nitrogen, not expressed by resting T-lymphocytes
additional information
granzyme A is produced by a variety of cell types involved in the immune response
additional information
most of the GZMA-positive cells (over 95%) in non-infected mice are positive for the NK1.1 surface marker with a small proportion of CD8+ and CD4+ T cells, indicating that in the absence of infection GZMA expression in lungs is mainly restricted to natural killer (NK) cells. Conversely, four weeks post-infection, percentage of NK1.1-positive GZMA-expressing cells decreases to 80%, due to the substantial increase observed in the percentage of GZMA-positive CD8+ and CD4+ T cells, (15% and 5%, respectively). In concurrence with these observations, both frequency and absolute number of CD4+ and CD8+ GZMA-expressing cells dramatically increase in lungs upon infection. Tuberculosis infection also leads to an increase in the number of GZMA-expressing NK cells
additional information
-
most of the GZMA-positive cells (over 95%) in non-infected mice are positive for the NK1.1 surface marker with a small proportion of CD8+ and CD4+ T cells, indicating that in the absence of infection GZMA expression in lungs is mainly restricted to natural killer (NK) cells. Conversely, four weeks post-infection, percentage of NK1.1-positive GZMA-expressing cells decreases to 80%, due to the substantial increase observed in the percentage of GZMA-positive CD8+ and CD4+ T cells, (15% and 5%, respectively). In concurrence with these observations, both frequency and absolute number of CD4+ and CD8+ GZMA-expressing cells dramatically increase in lungs upon infection. Tuberculosis infection also leads to an increase in the number of GZMA-expressing NK cells
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
additional information
-
the enzyme binds to natural basement membranes in a charge-dependent manner
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GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
malfunction
physiological function
evolution
-
the enzyme belongs to the granzyme serine protease family, key effector molecules expressed by cytotoxic lymphocytes. Peptide substrate specificity profile of mouse and human granzyme A, overview
physiological function
malfunction
even though granzyme A is expressed by cytotoxic cells from mouse lungs during pulmonary infection, its deficiency in knockout mice does not have an effect in the control of Mycobacterium tuberculosis infection
malfunction
phenotypic characterization of gzmA-/- regulatory T cells (Tregs) efficiently homing to secondary lymphoid organs, GzmA-/- Tregs home efficiently to secondary lymphoid organs, overview. No difference between wild-type and GZMA-/- mice in Treg numbers in spleen and peripheral lymph nodes. Enzyme-deficient gzmA-/- Tregs cannot efficiently protect from GvHD-related inflammation and organ destruction in the intestinal tract with relevant crypt apoptosis detected in the small and large intestine
malfunction
pneumonia is induced in wild-type and GzmA-deficient (GzmA-/-) mice by intranasal inoculation of Streptococcus pneumoniae. In separate experiments, wild-type and GzmA-/- mice are treated with natural killer (NK) cell depleting antibodies. Upon infection, GzmA-/- mice show a better survival and lower bacterial counts in bronchoalveolar lavage fluid (BALF) and distant body sites compared to the wild-type mice. Although NK cells show strong GzmA expression, NK cell depletion does not influence bacterial loads in either wild-type or GzmA-/- mice. GzmA deficiency has little impact on lung pathology during late stage pneumococcal pneumonia
physiological function
wild-type and granzyme A-deficient mice eliminate the mouse pathogen Brucella microti from liver and spleen within 2 or 3 weeks, whereas the bacteria persist in mice lacking perforin or granzyme B as well as in mice depleted of Tc cells. Only gzmA-/- mice exhibit increased survival, which correlated with reduced proinflammatory cytokines, due to depletion of natural killer cells. Infection-related pathology, but not bacterial clearance, appears to require the enzyme
physiological function
granzyme A contributes to the early inflammatory response in the lung. Granzyme A (GzmA) plays an unfavorable role in host defense during pneumococcal pneumonia by a mechanism that does not depend on natural killer cells. GzmA enhances bacterial dissemination and mortality in pneumococcal pneumonia
physiological function
granzyme A is expressed in mouse lungs during Mycobacterium tuberculosis strain H37Rv infection but does not contribute to protection in vivo. Granzyme A does not have a crucial role in vivo in the protective response to tuberculosis
physiological function
granzyme A is required for regulatory T-cell mediated prevention of gastrointestinal graft-versus-host disease. Analysis of the role of granzyme A (GZMA) in a haploidentical murine graft-versus-host disease (GvHD) model using gzmA-/- donor regulatory T cells (Tregs) to clarify the functional relevance of GZMA for Treg-mediated suppression of GvHD. GZMA expressing Tregs protect against GvHD-related tissue damage of the intestine
physiological function
-
in filarial infection with Litomosoides sigmodontis, worm loads are significantly reduced in gzmA/gzmB and in gzmB knockout mice during the whole course of infection, but enhanced only early in gzmA knockout compared with wild-type mice. GzmA/gzmB deficiency is associated with a defense-promoting Th2 cytokine and Ab shift, enhanced early inflammatory gene expression, and a trend of reduced alternatively activated macrophage induction, whereas gzmA deficiency is linked with reduced inflammation and a trend toward increased alternatively activated macrophages
physiological function
-
the murine enzyme shows a high cytotoxic potential in P815 mastocytoma target cells with streptolysin O
UNIPROT
ENTRY NAME
ORGANISM
NO. OF AA
NO. OF TRANSM. HELICES
MOLECULAR WEIGHT[Da]
SOURCE
SEQUENCE
LOCALIZATION PREDICTION
The reliability class of the localization prediction ranges from 1 (very reliable) to 5 (not reliable).
The reliability class of the localization prediction ranges from 1 (very reliable) to 5 (not reliable). GRAA_MOUSE
260
0
28599
Swiss-Prot
Secretory Pathway (Reliability: 2)
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
30000
-
x * 60000, mouse, SDS-PAGE under nonreducing condition, x * 30000, SDS-PAGE under reducing condition, mouse
60000
-
x * 60000, mouse, SDS-PAGE under nonreducing condition, x * 30000, SDS-PAGE under reducing condition, mouse
SUBUNIT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
?
-
x * 60000, mouse, SDS-PAGE under nonreducing condition, x * 30000, SDS-PAGE under reducing condition, mouse
dimer
-
enzyme occurs as disulfide-linked homodimer of 60000 (mouse) and 50000 (human) with 2 catalytic sites, under reducing condition the MWs shift to 35000 and 25000, respectively
PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
additional information
additional information
cell depleted bone marrow cells (TCD BM) and isolated T cell populations of wild type (WT) and gzmA-/- C57/BL6 donor mice are transferred into the BALB/c recipient mice after lethal irradiation. Immune tolerant and GvHD mice are monitored comparatively after adoptive T cell transfer for incidence, severity and clinical manifestation of GvHD by clinical and histopathological grading. After irradiation and transplantation the body weight of recipient mice declines in all treatment groups and increases again one week after transplantation. But two weeks after transplantation, mice from the GvHD group continuously lost weight in contrast to the immune tolerant groups. Histopathological investigations confirm a severe inflammation especially in the small and large intestine as GvHD target organs. Enzyme-deficient gzmA-/- Tregs cannot efficiently protect from GvHD-related inflammation and organ destruction in the intestinal tract with relevant crypt apoptosis detected in the small and large intestine
additional information
-
cell depleted bone marrow cells (TCD BM) and isolated T cell populations of wild type (WT) and gzmA-/- C57/BL6 donor mice are transferred into the BALB/c recipient mice after lethal irradiation. Immune tolerant and GvHD mice are monitored comparatively after adoptive T cell transfer for incidence, severity and clinical manifestation of GvHD by clinical and histopathological grading. After irradiation and transplantation the body weight of recipient mice declines in all treatment groups and increases again one week after transplantation. But two weeks after transplantation, mice from the GvHD group continuously lost weight in contrast to the immune tolerant groups. Histopathological investigations confirm a severe inflammation especially in the small and large intestine as GvHD target organs. Enzyme-deficient gzmA-/- Tregs cannot efficiently protect from GvHD-related inflammation and organ destruction in the intestinal tract with relevant crypt apoptosis detected in the small and large intestine
additional information
generation of GzmA-/- knockout mice, backcrossed into the C57BL/6 background more than 10 times
additional information
-
generation of GzmA-/- knockout mice, backcrossed into the C57BL/6 background more than 10 times
PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
APPLICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
medicine
the protease may be a therapeutic target for the prevention of bacterial sepsis without affecting immune control of the pathogen
medicine
medicine
-
cytolytic T-lymphocytes from enzyme or granzyme B deficient mice similarly induce early proapoptotic features such as phosphatidyl serine exposure on plasma membrane, or reactive oxygen radical generation, though with distinct kinetics. Cytolytic T-lymphocytes from granzyme A, but not granzyme B deficient animals activate caspase 3 and 9. All granzyme-induced apoptotic features depend critically on perforin
medicine
-
proinflammatory gzmA and anti-inflammatory gzmB are novel modulators of the Th1/2 balance and defense in helminth infection
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Odake, S.; Kam, C.M.; Narasimhan, L.; Poe, M.; Blake, J.T.; Krahenbuhl, O.; Tschopp, J.; Powers, J.C.
Human and murine cytotoxic T lymphocyte serine proteases: subsite mapping with peptide thioester substrates and inhibition of enzyme activity and cytolysis by isocoumarins
Biochemistry
30
2217-2227
1991
Homo sapiens, Mus musculus
Simon, M.M.; Hoschutzky, H.; Fruth, U.; Simon, H.G.; Kramer, M.D.
Purification and characterization of a T cell specific serine proteinase (TSP-1) from cloned cytolytic T lymphocytes
EMBO J.
5
3267-3274
1986
Mus musculus
Simon, M.M.; Kramer, M.D.
Granzyme A
Methods Enzymol.
244
68-79
1994
Homo sapiens, Mus musculus
Vettel, U.; Brunner, G.; Bar-Shavit, R.; Vlodavsky, I.; Kramer, M.D.
Charge-dependent binding of granzyme A (MTSP-1) to basement membranes
Eur. J. Immunol.
23
279-282
1993
Mus musculus
Pardo, J.; Bosque, A.; Brehm, R.; Wallich, R.; Naval, J.; Mullbacher, A.; Anel, A.; Simon, M.M.
Apoptotic pathways are selectively activated by granzyme A and/or granzyme B in CTL-mediated target cell lysis
J. Cell Biol.
167
457-468
2004
Mus musculus
Baschuk, N.; Utermoehlen, O.; Gugel, R.; Warnecke, G.; Karow, U.; Paulsen, D.; Brombacher, F.; Kroenke, M.; Deppert, W.
Interleukin-4 impairs granzyme-mediated cytotoxicity of Simian virus 40 large tumor antigen-specific CTL in BALB/c mice
Cancer Immunol. Immunother.
56
1625-1636
2007
Mus musculus (P11032)
Kaiserman, D.; Bird, C.H.; Sun, J.; Matthews, A.; Ung, K.; Whisstock, J.C.; Thompson, P.E.; Trapani, J.A.; Bird, P.I.
The major human and mouse granzymes are structurally and functionally divergent
J. Cell Biol.
175
619-630
2006
Mus musculus (P11032), Mus musculus, Homo sapiens (P12544), Homo sapiens
Hartmann, W.; Marsland, B.J.; Otto, B.; Urny, J.; Fleischer, B.; Korten, S.
A novel and divergent role of granzyme A and B in resistance to helminth infection
J. Immunol.
186
2472-2481
2011
Mus musculus
Arias, M.A.; Jimenez de Baguees, M.P.; Aguilo, N.; Menao, S.; Hervas-Stubbs, S.; de Martino, A.; Alcaraz, A.; Simon, M.M.; Froelich, C.J.; Pardo, J.
Elucidating sources and roles of granzymes A and B during bacterial infection and sepsis
Cell Rep.
8
420-429
2014
Mus musculus (P11032), Mus musculus, Mus musculus B6 (P11032)
Kaiserman, D.; Stewart, S.E.; Plasman, K.; Gevaert, K.; Van Damme, P.; Bird, P.I.
Identification of Serpinb6b as a species-specific mouse granzyme A inhibitor suggests functional divergence between human and mouse granzyme A
J. Biol. Chem.
289
9408-9417
2014
Mus musculus, Homo sapiens (P12544), Homo sapiens
van den Boogaard, F.E.; van Gisbergen, K.P.; Vernooy, J.H.; Medema, J.P.; Roelofs, J.J.; van Zoelen, M.A.; Endeman, H.; Biesma, D.H.; Boon, L.; Vant Veer, C.; de Vos, A.F.; van der Poll, T.
Granzyme A impairs host defense during Streptococcus pneumoniae pneumonia
Am. J. Physiol. Lung Cell Mol. Physiol.
311
L507-L516
2016
Mus musculus (P11032), Homo sapiens (P12544), Homo sapiens, Mus musculus C57BL/6 (P11032)
Velaga, S.; Ukena, S.; Dringenberg, U.; Alter, C.; Pardo, J.; Kershaw, O.; Franzke, A.
Granzyme a is required for regulatory T-cell mediated prevention of gastrointestinal graft-versus-host disease
PLoS ONE
10
e0124927
2015
Mus musculus (P11032), Mus musculus
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