Phenotypes associated with this allele

• Allele Symbol: Cyrib^em1Erob
• Allele Name: endonuclease-mediated mutation 1, Ellen Robey
• Allele ID: MGI:7865346
• Summary: 1 genotype

Jump to	Allelic Composition	Genetic Background	Genotype ID
hm1	Cyrib^em1Erob/Cyrib^em1Erob	involves: C57BL/6J	MGI:8219506

Genotype
MGI:8219506

hm1

• Allelic Composition: Cyrib^em1Erob/Cyrib^em1Erob
• Genetic Background: involves: C57BL/6J

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

immune system

increased T cell apoptosis ( J:361791 )

• fleshly isolated naive CD8 T and CD4 T cells show a significantly higher frequency of 7AAD+ and Annexin V+ cells than wild-type cells

• a significantly increased ratio of BIM/Bcl-2 is detected in naive CD4 T cells at 6-8 weeks of age

increased thymocyte apoptosis ( J:361791 )

• immature (CD69^hiCD62L^lo) and semi-mature (CD69^loCD62L^lo) SP thymocytes show a 2-fold increase in cell death, as revealed by 7AAD/Annexin V staining

• a significantly increased ratio of BIM/Bcl-2 is detected in total thymocytes at 6-8 weeks of age

• however, the frequency of dead cells detected among mature (CD69^loCD62L^hi) SP thymocytes is normal

abnormal thymus cell ratio ( J:361791 )

• mice show a significant increase in the ratio of TCRbeta^hi CD4 SP cells to TCRbeta^hi CD8 SP in the thymus

• late-stage thymocytes (TCRbeta^hiCD69+ and TCRbeta^hiCD69-) show an increased ratio of CD4 single-positive (SP) to CD8 SP

• post-positive selection SP thymocytes (TCRbeta^hiCD5^hi) also show an increased ratio of CD4 SP to CD8 SP

abnormal thymocyte activation ( J:361791 )

• after TCR stimulation with anti-CD3epsilon and CD4 mAb, total thymocytes show prolonged increases in all downstream phosphorylation events tested, including ZAP-70, LAT, PLCgamma1, and ERK; PAK phosphorylation as also dramatically elevated

abnormal T cell differentiation ( J:361791 )

• mice show impaired thymocyte development of both CD4+ and CD8+ T cells, with a greater impact noted on the CD8+ T cell population

• analysis of bone marrow chimeras generated by injecting T cell-depleted CD45.2+ bone marrow cells into sublethally irradiated wild-type CD45.1+ mice (B6.SJL-Ptprc^a Pepc^b/BoyJ) indicates that impaired T cell development is predominantly thymocyte intrinsic

• thymocytes show an impaired post-positive selection process: the % of stage 2 thymocytes (TCRbeta^intCD69+), representing transitional double-positive (DP) cells undergoing TCR-mediated positive selection, is significantly increased, whereas the % of late-stage thymocytes including the post-positive selection (TCRbeta^hiCD69+) and mature thymocytes (TCRbeta^hiCD69-) is markedly reduced, resulting in an increased ratio of CD4 single-positive (SP) to CD8 SP among late-stage thymocytes

• moreover, the % of all early phase thymocyte populations (TCRbeta^loCD5^lo, TCRbeta^loCD5^int, TCRbeta^intCD5^hi) is significantly increased, whereas the % of post-positive selection SP thymocytes (TCRbeta^hiCD5^hi) is reduced, resulting in an increased ratio of CD4 SP to CD8 SP among TCRbeta^hiCD5^hi thymocytes

• a significantly lower % of mature SP TCRbeta^hiCD24^lo cells is detected among total live thymocytes

abnormal negative T cell selection ( J:361791 )

• double positive (DP) thymocytes undergo excessive negative selection

• however, the positive selection stage is unaffected

abnormal T cell clonal deletion ( J:361791 )

• in the thymus, the frequency of cleaved-caspase3+ TCRbeta^hiCD5^hi thymocytes undergoing clonal deletion is significantly higher than that in wild-type controls

• moreover, the frequencies of cleaved-caspase3+ CCR7- cells and cleaved- caspase3+ CCR7+ cells are significantly increased, suggesting that more thymocytes undergo clonal deletion in both the thymic cortex and medulla

• in contrast, the frequency of cleaved-caspase3+ TCRbeta-CD5- thymocytes undergoing death by neglect (i.e. failed positive selection) is normal

abnormal double-positive T cell morphology ( J:361791 )

• double positive (DP) thymocytes, but not CD4 SP or CD8 SP thymocytes, show upregulated surface expression of CD5 (a surrogate marker for TCR-signal strength in the thymus), suggesting that enhanced TCR-signaling strength is intrinsic to DP cells

abnormal intraepithelial T cell number ( J:361791 )

• mice show a significantly lower % of CD8alpha-alpha+ TCRalpha-beta+ intraepithelial lymphocytes (IELs) among IEL T cells in the small intestinal epithelium than wild-type controls (30% versus 60%, respectively)

• moreover, the frequency of gut natural IELs -- including both TCRgamma-delta+ IELs and CD8alpha-alpha+ TCRalpha-beta+ IELs -- among total live IELs is markedly reduced, whereas the relative frequency of induced IELs (CD8alpha-beta+TCRalpha-beta+ IELs) is increased

• however, no decrease is noted in the frequencies and numbers of two distinct CD8alpha-alpha IEL precursors in the thymus and the integrin expression of each IEL precursor is similar to that in wild-type controls

decreased T cell number ( J:361791 )

• mice develop severe T cell lymphopenia due to enhanced TCR-signaling in DP thymocytes

decreased thymocyte number ( J:361791 )

• consistent with excessive clonal deletion in the thymic cortex and medulla, the absolute numbers of immature (CD69^hiCD62L^lo) and mature (CD69^loCD62L^hi) CD8 SP and CD4 SP cells are significantly lower than in wild-type controls

decreased CD4-positive, alpha-beta T cell number ( J:361791 )

• both the frequency and number of peripheral CD4+ T cells and of TCRbeta^hi CD4 single-positive (SP) thymocytes are significantly decreased relative to those in wild-type controls

decreased CD8-positive, alpha-beta T cell number ( J:361791 )

• both the frequency and number of peripheral CD8+ T cells and of TCRbeta^hi CD8 SP thymocytes are significantly decreased relative to those in wild-type controls

• notably, the reduction in the number of peripheral CD8+ T cells is greater than that of CD4+ T cells

decreased gamma-delta intraepithelial T cell number ( J:361791 )

• mice show a significantly lower frequency of TCRgamma-delta+ IELs among total live IELs in the gut

decreased regulatory T cell number ( J:361791 )

• although the frequency of Foxp3+CD25+ Treg cells among lymphoid CD4+ T cells is slightly higher than that in wild-type peripheral lymph nodes (20% versus 16%, respectively), the absolute number of Foxp3+ Treg cells in peripheral lymph nodes is ~80% of that in wild-type controls

• however, the frequency of CD1d-tetramer+ invariant natural killer T cells (iNKT cells) in the liver is normal

abnormal lymph node cell ratio ( J:361791 )

• mice show a significant increase in the ratio of CD4+ T cells to CD8+ T cells in peripheral lymph nodes and mesenteric lymph node, but no change in spleen

hematopoietic system

increased T cell apoptosis ( J:361791 )

• fleshly isolated naive CD8 T and CD4 T cells show a significantly higher frequency of 7AAD+ and Annexin V+ cells than wild-type cells

• a significantly increased ratio of BIM/Bcl-2 is detected in naive CD4 T cells at 6-8 weeks of age

increased thymocyte apoptosis ( J:361791 )

• immature (CD69^hiCD62L^lo) and semi-mature (CD69^loCD62L^lo) SP thymocytes show a 2-fold increase in cell death, as revealed by 7AAD/Annexin V staining

• a significantly increased ratio of BIM/Bcl-2 is detected in total thymocytes at 6-8 weeks of age

• however, the frequency of dead cells detected among mature (CD69^loCD62L^hi) SP thymocytes is normal

abnormal thymus cell ratio ( J:361791 )

• mice show a significant increase in the ratio of TCRbeta^hi CD4 SP cells to TCRbeta^hi CD8 SP in the thymus

• late-stage thymocytes (TCRbeta^hiCD69+ and TCRbeta^hiCD69-) show an increased ratio of CD4 single-positive (SP) to CD8 SP

• post-positive selection SP thymocytes (TCRbeta^hiCD5^hi) also show an increased ratio of CD4 SP to CD8 SP

abnormal thymocyte activation ( J:361791 )

• after TCR stimulation with anti-CD3epsilon and CD4 mAb, total thymocytes show prolonged increases in all downstream phosphorylation events tested, including ZAP-70, LAT, PLCgamma1, and ERK; PAK phosphorylation as also dramatically elevated

abnormal T cell differentiation ( J:361791 )

• mice show impaired thymocyte development of both CD4+ and CD8+ T cells, with a greater impact noted on the CD8+ T cell population

• analysis of bone marrow chimeras generated by injecting T cell-depleted CD45.2+ bone marrow cells into sublethally irradiated wild-type CD45.1+ mice (B6.SJL-Ptprc^a Pepc^b/BoyJ) indicates that impaired T cell development is predominantly thymocyte intrinsic

• thymocytes show an impaired post-positive selection process: the % of stage 2 thymocytes (TCRbeta^intCD69+), representing transitional double-positive (DP) cells undergoing TCR-mediated positive selection, is significantly increased, whereas the % of late-stage thymocytes including the post-positive selection (TCRbeta^hiCD69+) and mature thymocytes (TCRbeta^hiCD69-) is markedly reduced, resulting in an increased ratio of CD4 single-positive (SP) to CD8 SP among late-stage thymocytes

• moreover, the % of all early phase thymocyte populations (TCRbeta^loCD5^lo, TCRbeta^loCD5^int, TCRbeta^intCD5^hi) is significantly increased, whereas the % of post-positive selection SP thymocytes (TCRbeta^hiCD5^hi) is reduced, resulting in an increased ratio of CD4 SP to CD8 SP among TCRbeta^hiCD5^hi thymocytes

• a significantly lower % of mature SP TCRbeta^hiCD24^lo cells is detected among total live thymocytes

abnormal negative T cell selection ( J:361791 )

• double positive (DP) thymocytes undergo excessive negative selection

• however, the positive selection stage is unaffected

abnormal T cell clonal deletion ( J:361791 )

• in the thymus, the frequency of cleaved-caspase3+ TCRbeta^hiCD5^hi thymocytes undergoing clonal deletion is significantly higher than that in wild-type controls

• moreover, the frequencies of cleaved-caspase3+ CCR7- cells and cleaved- caspase3+ CCR7+ cells are significantly increased, suggesting that more thymocytes undergo clonal deletion in both the thymic cortex and medulla

• in contrast, the frequency of cleaved-caspase3+ TCRbeta-CD5- thymocytes undergoing death by neglect (i.e. failed positive selection) is normal

abnormal double-positive T cell morphology ( J:361791 )

• double positive (DP) thymocytes, but not CD4 SP or CD8 SP thymocytes, show upregulated surface expression of CD5 (a surrogate marker for TCR-signal strength in the thymus), suggesting that enhanced TCR-signaling strength is intrinsic to DP cells

abnormal intraepithelial T cell number ( J:361791 )

• mice show a significantly lower % of CD8alpha-alpha+ TCRalpha-beta+ intraepithelial lymphocytes (IELs) among IEL T cells in the small intestinal epithelium than wild-type controls (30% versus 60%, respectively)

• moreover, the frequency of gut natural IELs -- including both TCRgamma-delta+ IELs and CD8alpha-alpha+ TCRalpha-beta+ IELs -- among total live IELs is markedly reduced, whereas the relative frequency of induced IELs (CD8alpha-beta+TCRalpha-beta+ IELs) is increased

• however, no decrease is noted in the frequencies and numbers of two distinct CD8alpha-alpha IEL precursors in the thymus and the integrin expression of each IEL precursor is similar to that in wild-type controls

decreased T cell number ( J:361791 )

• mice develop severe T cell lymphopenia due to enhanced TCR-signaling in DP thymocytes

decreased thymocyte number ( J:361791 )

• consistent with excessive clonal deletion in the thymic cortex and medulla, the absolute numbers of immature (CD69^hiCD62L^lo) and mature (CD69^loCD62L^hi) CD8 SP and CD4 SP cells are significantly lower than in wild-type controls

decreased CD4-positive, alpha-beta T cell number ( J:361791 )

• both the frequency and number of peripheral CD4+ T cells and of TCRbeta^hi CD4 single-positive (SP) thymocytes are significantly decreased relative to those in wild-type controls

decreased CD8-positive, alpha-beta T cell number ( J:361791 )

• both the frequency and number of peripheral CD8+ T cells and of TCRbeta^hi CD8 SP thymocytes are significantly decreased relative to those in wild-type controls

• notably, the reduction in the number of peripheral CD8+ T cells is greater than that of CD4+ T cells

decreased gamma-delta intraepithelial T cell number ( J:361791 )

• mice show a significantly lower frequency of TCRgamma-delta+ IELs among total live IELs in the gut

decreased regulatory T cell number ( J:361791 )

• although the frequency of Foxp3+CD25+ Treg cells among lymphoid CD4+ T cells is slightly higher than that in wild-type peripheral lymph nodes (20% versus 16%, respectively), the absolute number of Foxp3+ Treg cells in peripheral lymph nodes is ~80% of that in wild-type controls

• however, the frequency of CD1d-tetramer+ invariant natural killer T cells (iNKT cells) in the liver is normal

endocrine/exocrine glands

increased thymocyte apoptosis ( J:361791 )

• immature (CD69^hiCD62L^lo) and semi-mature (CD69^loCD62L^lo) SP thymocytes show a 2-fold increase in cell death, as revealed by 7AAD/Annexin V staining

• a significantly increased ratio of BIM/Bcl-2 is detected in total thymocytes at 6-8 weeks of age

• however, the frequency of dead cells detected among mature (CD69^loCD62L^hi) SP thymocytes is normal

abnormal thymus cell ratio ( J:361791 )

• mice show a significant increase in the ratio of TCRbeta^hi CD4 SP cells to TCRbeta^hi CD8 SP in the thymus

• late-stage thymocytes (TCRbeta^hiCD69+ and TCRbeta^hiCD69-) show an increased ratio of CD4 single-positive (SP) to CD8 SP

• post-positive selection SP thymocytes (TCRbeta^hiCD5^hi) also show an increased ratio of CD4 SP to CD8 SP

decreased thymocyte number ( J:361791 )

• consistent with excessive clonal deletion in the thymic cortex and medulla, the absolute numbers of immature (CD69^hiCD62L^lo) and mature (CD69^loCD62L^hi) CD8 SP and CD4 SP cells are significantly lower than in wild-type controls

abnormal thymocyte activation ( J:361791 )

• after TCR stimulation with anti-CD3epsilon and CD4 mAb, total thymocytes show prolonged increases in all downstream phosphorylation events tested, including ZAP-70, LAT, PLCgamma1, and ERK; PAK phosphorylation as also dramatically elevated

cellular

increased T cell apoptosis ( J:361791 )

• fleshly isolated naive CD8 T and CD4 T cells show a significantly higher frequency of 7AAD+ and Annexin V+ cells than wild-type cells

• a significantly increased ratio of BIM/Bcl-2 is detected in naive CD4 T cells at 6-8 weeks of age

increased thymocyte apoptosis ( J:361791 )

• immature (CD69^hiCD62L^lo) and semi-mature (CD69^loCD62L^lo) SP thymocytes show a 2-fold increase in cell death, as revealed by 7AAD/Annexin V staining

• a significantly increased ratio of BIM/Bcl-2 is detected in total thymocytes at 6-8 weeks of age

• however, the frequency of dead cells detected among mature (CD69^loCD62L^hi) SP thymocytes is normal