Phenotypes associated with this allele

• Allele Symbol: Map4k2^{tm1c(KOMP)Wtsi}
• Allele Name: targeted mutation 1c, Wellcome Trust Sanger Institute
• Allele ID: MGI:8314967
• Summary: 2 genotypes

Jump to	Allelic Composition	Genetic Background	Genotype ID
cn1	Map4k2^tm1c(KOMP)Wtsi/Map4k2^+ Tg(Foxp3-EGFP/icre)1aJbs/0	B6.Cg-Map4k2^tm1c(KOMP)Wtsi Tg(Foxp3-EGFP/icre)1aJbs	MGI:8399075
cn2	Map4k2^tm1c(KOMP)Wtsi/Map4k2^tm1c(KOMP)Wtsi Tg(Cd4-cre)1Cwi/0	B6.Cg-Tg(Cd4-cre)1Cwi Map4k2^tm1c(KOMP)Wtsi	MGI:8399069

Genotype
MGI:8399075

cn1

• Allelic Composition: Map4k2^{tm1c(KOMP)Wtsi}/Map4k2⁺; Tg(Foxp3-EGFP/icre)1aJbs/0
• Genetic Background: B6.Cg-Map4k2^{tm1c(KOMP)Wtsi} Tg(Foxp3-EGFP/icre)1aJbs

• ♀: phenotype observed in females
• ♂: phenotype observed in males
• N: normal phenotype

immune system

decreased regulatory T cell number ( J:382684 )

• mice show a significant reduction in the population of regulatory T cells (Treg, CD4+FOXP3+) in the spleen

abnormal CD4-positive, CD25-positive, alpha-beta regulatory T cell morphology ( J:382684 )

• splenic CD4+ CD25+ T cells show significantly reduced protein levels of FOXP3 (a Treg master transcription factor)

increased susceptibility to experimental autoimmune encephalomyelitis ( J:382684 )

• in the MOG-induced EAE model, mice exhibit sustained EAE inflammation during the remission phase, with significantly higher clinical scores and serum IL-17A, IL-6, and IFN-gamma levels and a significant reduction in serum IL-10 levels and infiltrating Treg cells in brain tissue, similar to B6.Cg-Tg(Cd4-cre)1Cwi Map4k2^{tm1c(KOMP)Wtsi} mice

hematopoietic system

decreased regulatory T cell number ( J:382684 )

• mice show a significant reduction in the population of regulatory T cells (Treg, CD4+FOXP3+) in the spleen

abnormal CD4-positive, CD25-positive, alpha-beta regulatory T cell morphology ( J:382684 )

• splenic CD4+ CD25+ T cells show significantly reduced protein levels of FOXP3 (a Treg master transcription factor)

neoplasm

abnormal tumor pathology ( J:382684 )

• in the syngeneic KPC pancreatic cancer model, tumor-bearing mice established by s.c. injection of pancreatic cancer cells from KPC (Kras^tm4Tyj/Kras⁺ Trp53^tm2Tyj/Trp53⁺ Tg(Pdx1-cre)6Tuv/0) mice and then i.p. injected with anti-PD-1 antibody show a significant reduction of tumor-infiltrating Treg (CD4+ FOXP3+) cells in tumor tissues; similarly, the % of CTLA4+ CD8+ (exhausted) cytotoxic T cells is also reduced in tumor tissues

• in contrast, the tumor-infiltrating CD8+ T cells are increased, suggesting that MAP4K2 deficiency leads to a reduced Treg population and induction of cytotoxic T cell population, contributing to the enhancement of anticancer immunity

decreased tumor growth/size ( J:382684 )

• in the syngeneic KPC pancreatic cancer model, tumor-bearing mice established by s.c. injection of pancreatic cancer cells from KPC mice and then i.p. injected with anti-PD-1 antibody show a significant decrease in tumor volume relative to anti-PD-1-treated control mice

Genotype
MGI:8399069

cn2

• Allelic Composition: Map4k2^{tm1c(KOMP)Wtsi}/Map4k2^{tm1c(KOMP)Wtsi}; Tg(Cd4-cre)1Cwi/0
• Genetic Background: B6.Cg-Tg(Cd4-cre)1Cwi Map4k2^{tm1c(KOMP)Wtsi}

immune system

immune system phenotype ( J:382684 )

N • 4-week-old mice show normal CD4+ and CD8+ T cell development and thymic negative selection

N • 24-week-old mice do NOT exhibit spontaneous autoimmune symptoms and have normal serum levels of autoantibodies, including anti-ANA, anti-double stranded DNA (dsDNA), and rheumatoid factor (RF)

abnormal T cell differentiation ( J:382684 )

• expression of Foxp3 (a Treg master transcription factor) is significantly decreased in T cells isolated from the spleen and lymph nodes; numbers of Foxp3+ T cells are decreased

• mRNA levels of Treg signature genes, such as Ctla4, Pdcd1 (Pd-1), Il10, and Il2ra (Cd25), are significantly decreased in T cells

• flow cytometry analyses confirm reduction of Treg markers CTLA4, IKZF2 (Helios), and IL2RA (CD25) and effector Treg markers (CD44 and CD62L) in T cells; however, CD25 protein levels in Treg (CD4+FOXP3+) cells are normal

• ratios of individual introns of Foxp3 pre-mRNA to Foxp3 mRNA levels are increased in in vitro differentiated Treg cells, suggesting reduced Foxp3 mRNA splicing

• reduction of FOXP3 protein levels in T cells is reversed by overexpression of DDX39B phosphomimetic (T389D) mutant protein in the absence of TGF-beta stimulation

abnormal CD4-positive T cell differentiation ( J:382684 )

• upon TGF-beta stimulation, splenic CD4+ T cells isolated from 8-week-old mice show reduced in vitro differentiation into Treg cells (CD4+FOXP3+)

• however, in vitro differentiation of Th1, Th2, and Th17 is unaffected

decreased regulatory T cell number ( J:382684 )

• 4-week-old mice show a significant reduction in the population of regulatory T cells (Treg, CD4+FOXP3+) in the spleen and lymph nodes but not in the thymus

abnormal regulatory T cell physiology ( J:382684 )

• in a co-culture assay, Treg cells from 8-week-old mice exhibit reduced suppressive function, failing to inhibit the proliferation of CFSE-labeled wild-type effector T cells

• however, TCR-induced T cell proliferation of effector T cells is normal

increased susceptibility to experimental autoimmune encephalomyelitis ( J:382684 )

• in the MOG-induced EAE model, the clinical score is relatively normal during the acute phase but remains high during the remission phase, unlike in wild-type controls; serum levels of proinflammatory cytokines (IL-17A, IL-6, and IFN-gamma) are significantly elevated whereas the level of anti-proinflammatory cytokine IL-10 is significantly decreased, and CNS-infiltrating and brain tissue levels of Treg cells are reduced whereas levels of infiltrating Th17 cells are increased, indicating sustained inflammation during EAE remission

• moreover, in vitro MOG-restimulated IL-17A, IL-6, and IFN-gamma production is increased in lymph node T cells isolated from MOG-immunized mice whereas IL-10 production is reduced

hematopoietic system

abnormal T cell differentiation ( J:382684 )

• expression of Foxp3 (a Treg master transcription factor) is significantly decreased in T cells isolated from the spleen and lymph nodes; numbers of Foxp3+ T cells are decreased

• mRNA levels of Treg signature genes, such as Ctla4, Pdcd1 (Pd-1), Il10, and Il2ra (Cd25), are significantly decreased in T cells

• flow cytometry analyses confirm reduction of Treg markers CTLA4, IKZF2 (Helios), and IL2RA (CD25) and effector Treg markers (CD44 and CD62L) in T cells; however, CD25 protein levels in Treg (CD4+FOXP3+) cells are normal

• ratios of individual introns of Foxp3 pre-mRNA to Foxp3 mRNA levels are increased in in vitro differentiated Treg cells, suggesting reduced Foxp3 mRNA splicing

• reduction of FOXP3 protein levels in T cells is reversed by overexpression of DDX39B phosphomimetic (T389D) mutant protein in the absence of TGF-beta stimulation

abnormal CD4-positive T cell differentiation ( J:382684 )

• upon TGF-beta stimulation, splenic CD4+ T cells isolated from 8-week-old mice show reduced in vitro differentiation into Treg cells (CD4+FOXP3+)

• however, in vitro differentiation of Th1, Th2, and Th17 is unaffected

decreased regulatory T cell number ( J:382684 )

• 4-week-old mice show a significant reduction in the population of regulatory T cells (Treg, CD4+FOXP3+) in the spleen and lymph nodes but not in the thymus

abnormal regulatory T cell physiology ( J:382684 )

• in a co-culture assay, Treg cells from 8-week-old mice exhibit reduced suppressive function, failing to inhibit the proliferation of CFSE-labeled wild-type effector T cells

• however, TCR-induced T cell proliferation of effector T cells is normal

neoplasm

abnormal tumor pathology ( J:382684 )

• in the syngeneic KPC pancreatic cancer model, tumor-bearing mice established by s.c. injection of pancreatic cancer cells from KPC (Kras^tm4Tyj/Kras⁺ Trp53^tm2Tyj/Trp53⁺ Tg(Pdx1-cre)6Tuv/0) mice and then i.p. injected with either anti-PD-1 antibody or IgG control antibody show a drastic reduction of tumor-infiltrating Treg (CD4+ FOXP3+) cells in tumor tissues; similarly, the % of CTLA4+ CD8+ (exhausted) cytotoxic T cells is also reduced in tumor tissues

• IHC assays show that DDX39B proteins are mainly localized in the cytoplasm of FOXP3+ T cells in tumor tissues from tumor-bearing mice, unlike in control mice where DDX39B proteins are largely localized in the nucleus

• in adoptive transfer experiments, recipient mice transferred with Treg cells also exhibit a decrease of tumor-infiltrating Treg cells and exhausted (CTLA-4+) CD8+ T cells in tumor tissues

decreased tumor growth/size ( J:382684 )

• in the syngeneic KPC pancreatic cancer model, tumor-bearing mice established by s.c. injection of pancreatic cancer cells from KPC mice and then i.p. injected with either anti-PD-1 antibody or IgG control antibody show a significant decrease in tumor volume relative to anti-IgG treated control mice

• adoptive transfer of Treg cells into irradiated recipient mice followed by injection of KPC tumor cells and treatment of tumor-bearing mice with anti-PD-1 antibody results in reduced tumor volumes relative to those in recipient mice transferred with wild-type Treg cells