Loss of T cell and B cell quiescence precedes the onset of microbial flora-dependent wasting disease and intestinal inflammation in Gimap5-deficient mice

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Loss of T cell and B cell quiescence precedes the onset of microbial flora-dependent wasting disease and intestinal inflammation in Gimap5-deficient mice. / Barnes, Michael J; Aksoylar, Halil; Krebs, Philippe et al.
In: Journal of Immunology, Vol. 184, No. 7, 01.04.2010, p. 3743-54.

Research output: Contribution to Journal/Magazine › Journal article › peer-review

Harvard

Barnes, MJ, Aksoylar, H, Krebs, P, Bourdeau, T, Arnold, CN, Xia, Y, Khovananth, K, Engel, I, Sovath, S, Lampe, K, Laws, E, Saunders, A, Butcher, GW, Kronenberg, M, Steinbrecher, K, Hildeman, D, Grimes, HL, Beutler, B & Hoebe, K 2010, 'Loss of T cell and B cell quiescence precedes the onset of microbial flora-dependent wasting disease and intestinal inflammation in Gimap5-deficient mice', Journal of Immunology, vol. 184, no. 7, pp. 3743-54. https://doi.org/10.4049/jimmunol.0903164

APA

Barnes, M. J., Aksoylar, H., Krebs, P., Bourdeau, T., Arnold, C. N., Xia, Y., Khovananth, K., Engel, I., Sovath, S., Lampe, K., Laws, E., Saunders, A., Butcher, G. W., Kronenberg, M., Steinbrecher, K., Hildeman, D., Grimes, H. L., Beutler, B., & Hoebe, K. (2010). Loss of T cell and B cell quiescence precedes the onset of microbial flora-dependent wasting disease and intestinal inflammation in Gimap5-deficient mice. Journal of Immunology, 184(7), 3743-54. https://doi.org/10.4049/jimmunol.0903164

Vancouver

Barnes MJ, Aksoylar H, Krebs P, Bourdeau T, Arnold CN, Xia Y et al. Loss of T cell and B cell quiescence precedes the onset of microbial flora-dependent wasting disease and intestinal inflammation in Gimap5-deficient mice. Journal of Immunology. 2010 Apr 1;184(7):3743-54. doi: 10.4049/jimmunol.0903164

Author

Barnes, Michael J ; Aksoylar, Halil ; Krebs, Philippe et al. / Loss of T cell and B cell quiescence precedes the onset of microbial flora-dependent wasting disease and intestinal inflammation in Gimap5-deficient mice. In: Journal of Immunology. 2010 ; Vol. 184, No. 7. pp. 3743-54.

Bibtex

@article{63fa482775ba4fa798c47446ae537ed1,

title = "Loss of T cell and B cell quiescence precedes the onset of microbial flora-dependent wasting disease and intestinal inflammation in Gimap5-deficient mice",

abstract = "Homeostatic control of the immune system involves mechanisms that ensure the self-tolerance, survival and quiescence of hematopoietic-derived cells. In this study, we demonstrate that the GTPase of immunity associated protein (Gimap)5 regulates these processes in lymphocytes and hematopoietic progenitor cells. As a consequence of a recessive N-ethyl-N-nitrosourea-induced germline mutation in the P-loop of Gimap5, lymphopenia, hepatic extramedullary hematopoiesis, weight loss, and intestinal inflammation occur in homozygous mutant mice. Irradiated fetal liver chimeric mice reconstituted with Gimap5-deficient cells lose weight and become lymphopenic, demonstrating a hematopoietic cell-intrinsic function for Gimap5. Although Gimap5-deficient CD4(+) T cells and B cells appear to undergo normal development, they fail to proliferate upon Ag-receptor stimulation although NF-kappaB, MAP kinase and Akt activation occur normally. In addition, in Gimap5-deficient mice, CD4(+) T cells adopt a CD44(high)CD62L(low)CD69(low) phenotype and show reduced IL-7ralpha expression, and T-dependent and T-independent B cell responses are abrogated. Thus, Gimap5-deficiency affects a noncanonical signaling pathway required for Ag-receptor-induced proliferation and lymphocyte quiescence. Antibiotic-treatment or the adoptive transfer of Rag-sufficient splenocytes ameliorates intestinal inflammation and weight loss, suggesting that immune responses triggered by microbial flora causes the morbidity in Gimap5-deficient mice. These data establish Gimap5 as a key regulator of hematopoietic integrity and lymphocyte homeostasis.",

keywords = "Animals, B-Lymphocyte Subsets/immunology, B-Lymphocytes/immunology, Colitis/genetics, Female, GTP Phosphohydrolases/genetics, GTP-Binding Proteins, Hematopoiesis/genetics, Hematopoietic Stem Cells/immunology, Homeostasis/genetics, Immunoblotting, Inflammation/genetics, Intestines/immunology, Liver Diseases/genetics, Male, Mice, Mice, Inbred C57BL, Mice, Mutant Strains, Self Tolerance/immunology, Signal Transduction/genetics, T-Lymphocyte Subsets/immunology, T-Lymphocytes/immunology, Wasting Syndrome/genetics",

author = "Barnes, {Michael J} and Halil Aksoylar and Philippe Krebs and Tristan Bourdeau and Arnold, {Carrie N} and Yu Xia and Kevin Khovananth and Isaac Engel and Sosathya Sovath and Kristin Lampe and Eleana Laws and Amy Saunders and Butcher, {Geoffrey W} and Mitchell Kronenberg and Kris Steinbrecher and David Hildeman and Grimes, {H Leighton} and Bruce Beutler and Kasper Hoebe",

year = "2010",

month = apr,

day = "1",

doi = "10.4049/jimmunol.0903164",

language = "English",

volume = "184",

pages = "3743--54",

journal = "Journal of Immunology",

issn = "0022-1767",

publisher = "American Association of Immunologists",

number = "7",

}

RIS

TY - JOUR

T1 - Loss of T cell and B cell quiescence precedes the onset of microbial flora-dependent wasting disease and intestinal inflammation in Gimap5-deficient mice

AU - Barnes, Michael J

AU - Aksoylar, Halil

AU - Krebs, Philippe

AU - Bourdeau, Tristan

AU - Arnold, Carrie N

AU - Xia, Yu

AU - Khovananth, Kevin

AU - Engel, Isaac

AU - Sovath, Sosathya

AU - Lampe, Kristin

AU - Laws, Eleana

AU - Saunders, Amy

AU - Butcher, Geoffrey W

AU - Kronenberg, Mitchell

AU - Steinbrecher, Kris

AU - Hildeman, David

AU - Grimes, H Leighton

AU - Beutler, Bruce

AU - Hoebe, Kasper

PY - 2010/4/1

Y1 - 2010/4/1

N2 - Homeostatic control of the immune system involves mechanisms that ensure the self-tolerance, survival and quiescence of hematopoietic-derived cells. In this study, we demonstrate that the GTPase of immunity associated protein (Gimap)5 regulates these processes in lymphocytes and hematopoietic progenitor cells. As a consequence of a recessive N-ethyl-N-nitrosourea-induced germline mutation in the P-loop of Gimap5, lymphopenia, hepatic extramedullary hematopoiesis, weight loss, and intestinal inflammation occur in homozygous mutant mice. Irradiated fetal liver chimeric mice reconstituted with Gimap5-deficient cells lose weight and become lymphopenic, demonstrating a hematopoietic cell-intrinsic function for Gimap5. Although Gimap5-deficient CD4(+) T cells and B cells appear to undergo normal development, they fail to proliferate upon Ag-receptor stimulation although NF-kappaB, MAP kinase and Akt activation occur normally. In addition, in Gimap5-deficient mice, CD4(+) T cells adopt a CD44(high)CD62L(low)CD69(low) phenotype and show reduced IL-7ralpha expression, and T-dependent and T-independent B cell responses are abrogated. Thus, Gimap5-deficiency affects a noncanonical signaling pathway required for Ag-receptor-induced proliferation and lymphocyte quiescence. Antibiotic-treatment or the adoptive transfer of Rag-sufficient splenocytes ameliorates intestinal inflammation and weight loss, suggesting that immune responses triggered by microbial flora causes the morbidity in Gimap5-deficient mice. These data establish Gimap5 as a key regulator of hematopoietic integrity and lymphocyte homeostasis.

AB - Homeostatic control of the immune system involves mechanisms that ensure the self-tolerance, survival and quiescence of hematopoietic-derived cells. In this study, we demonstrate that the GTPase of immunity associated protein (Gimap)5 regulates these processes in lymphocytes and hematopoietic progenitor cells. As a consequence of a recessive N-ethyl-N-nitrosourea-induced germline mutation in the P-loop of Gimap5, lymphopenia, hepatic extramedullary hematopoiesis, weight loss, and intestinal inflammation occur in homozygous mutant mice. Irradiated fetal liver chimeric mice reconstituted with Gimap5-deficient cells lose weight and become lymphopenic, demonstrating a hematopoietic cell-intrinsic function for Gimap5. Although Gimap5-deficient CD4(+) T cells and B cells appear to undergo normal development, they fail to proliferate upon Ag-receptor stimulation although NF-kappaB, MAP kinase and Akt activation occur normally. In addition, in Gimap5-deficient mice, CD4(+) T cells adopt a CD44(high)CD62L(low)CD69(low) phenotype and show reduced IL-7ralpha expression, and T-dependent and T-independent B cell responses are abrogated. Thus, Gimap5-deficiency affects a noncanonical signaling pathway required for Ag-receptor-induced proliferation and lymphocyte quiescence. Antibiotic-treatment or the adoptive transfer of Rag-sufficient splenocytes ameliorates intestinal inflammation and weight loss, suggesting that immune responses triggered by microbial flora causes the morbidity in Gimap5-deficient mice. These data establish Gimap5 as a key regulator of hematopoietic integrity and lymphocyte homeostasis.

KW - Animals

KW - B-Lymphocyte Subsets/immunology

KW - B-Lymphocytes/immunology

KW - Colitis/genetics

KW - Female

KW - GTP Phosphohydrolases/genetics

KW - GTP-Binding Proteins

KW - Hematopoiesis/genetics

KW - Hematopoietic Stem Cells/immunology

KW - Homeostasis/genetics

KW - Immunoblotting

KW - Inflammation/genetics

KW - Intestines/immunology

KW - Liver Diseases/genetics

KW - Male

KW - Mice

KW - Mice, Inbred C57BL

KW - Mice, Mutant Strains

KW - Self Tolerance/immunology

KW - Signal Transduction/genetics

KW - T-Lymphocyte Subsets/immunology

KW - T-Lymphocytes/immunology

KW - Wasting Syndrome/genetics

U2 - 10.4049/jimmunol.0903164

DO - 10.4049/jimmunol.0903164

M3 - Journal article

C2 - 20190135

VL - 184

SP - 3743

EP - 3754

JO - Journal of Immunology

JF - Journal of Immunology

SN - 0022-1767

IS - 7

ER -

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