Targeted Disruption of the Interferon-gamma Receptor 2 Gene Results in Severe Immune Defects in Mice

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 1998 Jul 8

PMID 9653170

Citations 37

Authors

B Lu

C Ebensperger

Z Dembic

Y Wang

M Kvatyuk

T Lu

R L Coffman

S Pestka

P B Rothman

Affiliations

Soon will be listed here.

Abstract

To study the role of the interferon- (IFN) gammaR2 chain in IFN-gamma signaling and immune function, IFN-gammaR2-deficient mice have been generated and characterized. Cells derived from IFN-gammaR2 -/- mice are unable to activate either JAK/STAT signaling proteins or gene transcription in response to IFN-gamma. The lack of IFN-gamma responsiveness alters IFN-gamma-induced Ig class switching by B cells from these mice. In vitro cultures of T cells demonstrate that the T cells from the IFN-gammaR2 -/- mice have a defect in Th1 cell differentiation. The IFN-gammaR2 (-/-) mice also produce lower amounts of IFN-gamma in response to antigenic challenge. In addition, IFN-gammaR2 -/- mice are defective in contact hypersensitivity and are highly susceptible to infection by Listeria monocytogenes. These results demonstrate that the IFN-gammaR2 is essential for IFN-gamma-mediated immune responses in vivo.

Citing Articles

Endothelial Regulates Expression of Pulmonary Lymphatic Junctional and Inflammation Genes in Mouse Lungs Impacting Lymphatic Transport.

Chakraborty A, Kim A, Alabdullatif S, Campbell J, Alekseyev Y, Kaplan U Res Sq. 2024; .

PMID: 38343832 PMC: 10854286. DOI: 10.21203/rs.3.rs-3808970/v1.

The immune-adjunctive potential of recombinant LAB vector expressing murine IFNλ3 (MuIFNλ3) against Type A Influenza Virus (IAV) infection.

Yadav S, Varma A, Muralidharan A, Bhowmick S, Mondal S, Mallick A Gut Pathog. 2023; 15(1):53.

PMID: 37904242 PMC: 10617148. DOI: 10.1186/s13099-023-00578-5.

A single dominant locus restricts retrovirus replication in YBR/Ei mice.

Beilinson H, Sevilleja A, Spring J, Benavides F, Beilinson V, Neokosmidis N J Virol. 2023; 97(8):e0068523.

PMID: 37578238 PMC: 10506465. DOI: 10.1128/jvi.00685-23.

Myeloid cell responsiveness to interferon-gamma is sufficient for initial resistance to .

Eshleman E, Bortell N, McDermott D, Crisler W, Lenz L Curr Res Immunol. 2021; 1:1-9.

PMID: 34337387 PMC: 8323841. DOI: 10.1016/j.crimmu.2020.01.001.

Interferon-induced GTPases orchestrate host cell-autonomous defence against bacterial pathogens.

Rafeld H, Kolanus W, van Driel I, Hartland E Biochem Soc Trans. 2021; 49(3):1287-1297.

PMID: 34003245 PMC: 8286824. DOI: 10.1042/BST20200900.

References

Groux H, Sornasse T, Cottrez F, De Vries J, Coffman R, Roncarolo M . Induction of human T helper cell type 1 differentiation results in loss of IFN-gamma receptor beta-chain expression. J Immunol. 1997; 158(12):5627-31. View

Watling D, Guschin D, Muller M, Silvennoinen O, Witthuhn B, Quelle F . Complementation by the protein tyrosine kinase JAK2 of a mutant cell line defective in the interferon-gamma signal transduction pathway. Nature. 1993; 366(6451):166-70. DOI: 10.1038/366166a0. View

Szabo S, Dighe A, Gubler U, Murphy K . Regulation of the interleukin (IL)-12R beta 2 subunit expression in developing T helper 1 (Th1) and Th2 cells. J Exp Med. 1997; 185(5):817-24. PMC: 2196166. DOI: 10.1084/jem.185.5.817. View

Wang Z, Reiner S, Zheng S, Dalton D, Locksley R . CD4+ effector cells default to the Th2 pathway in interferon gamma-deficient mice infected with Leishmania major. J Exp Med. 1994; 179(4):1367-71. PMC: 2191434. DOI: 10.1084/jem.179.4.1367. View

Harada H, Kitagawa M, Tanaka N, Yamamoto H, Harada K, Ishihara M . Anti-oncogenic and oncogenic potentials of interferon regulatory factors-1 and -2. Science. 1993; 259(5097):971-4. DOI: 10.1126/science.8438157. View

Argetsinger L, Norstedt G, Billestrup N, White M . Growth hormone, interferon-gamma, and leukemia inhibitory factor utilize insulin receptor substrate-2 in intracellular signaling. J Biol Chem. 1996; 271(46):29415-21. DOI: 10.1074/jbc.271.46.29415. View

Ebensperger C, Rhee S, Muthukumaran G, Lembo D, Donnelly R, Pestka S . Genomic organization and promoter analysis of the gene ifngr2 encoding the second chain of the mouse interferon-gamma receptor. Scand J Immunol. 1996; 44(6):599-606. DOI: 10.1046/j.1365-3083.1996.d01-353.x. View

Huang S, Hendriks W, Althage A, Hemmi S, Bluethmann H, Kamijo R . Immune response in mice that lack the interferon-gamma receptor. Science. 1993; 259(5102):1742-5. DOI: 10.1126/science.8456301. View

Wen Z, Zhong Z, Darnell Jr J . Maximal activation of transcription by Stat1 and Stat3 requires both tyrosine and serine phosphorylation. Cell. 1995; 82(2):241-50. DOI: 10.1016/0092-8674(95)90311-9. View

10.

Dighe A, Campbell D, Hsieh C, Clarke S, Greaves D, Gordon S . Tissue-specific targeting of cytokine unresponsiveness in transgenic mice. Immunity. 1995; 3(5):657-66. DOI: 10.1016/1074-7613(95)90136-1. View

11.

Farrar M, Campbell J, Schreiber R . Identification of a functionally important sequence in the C terminus of the interferon-gamma receptor. Proc Natl Acad Sci U S A. 1992; 89(24):11706-10. PMC: 50625. DOI: 10.1073/pnas.89.24.11706. View

12.

Bach E, Szabo S, Dighe A, Ashkenazi A, Aguet M, Murphy K . Ligand-induced autoregulation of IFN-gamma receptor beta chain expression in T helper cell subsets. Science. 1995; 270(5239):1215-8. DOI: 10.1126/science.270.5239.1215. View

13.

Durbin J, Hackenmiller R, Simon M, Levy D . Targeted disruption of the mouse Stat1 gene results in compromised innate immunity to viral disease. Cell. 1996; 84(3):443-50. DOI: 10.1016/s0092-8674(00)81289-1. View

14.

Aguet M, Dembic Z, Merlin G . Molecular cloning and expression of the human interferon-gamma receptor. Cell. 1988; 55(2):273-80. DOI: 10.1016/0092-8674(88)90050-5. View

15.

Marsters S, Pennica D, Bach E, Schreiber R, Ashkenazi A . Interferon gamma signals via a high-affinity multisubunit receptor complex that contains two types of polypeptide chain. Proc Natl Acad Sci U S A. 1995; 92(12):5401-5. PMC: 41702. DOI: 10.1073/pnas.92.12.5401. View

16.

Lai S, Molden J, Liu K, Puck J, White M, Goldsmith M . Interleukin-4-specific signal transduction events are driven by homotypic interactions of the interleukin-4 receptor alpha subunit. EMBO J. 1996; 15(17):4506-14. PMC: 452180. View

17.

Sakatsume M, Finbloom D . Modulation of the expression of the IFN-gamma receptor beta-chain controls responsiveness to IFN-gamma in human peripheral blood T cells. J Immunol. 1996; 156(11):4160-6. View

18.

Singh K, Balligand J, Fischer T, Smith T, Kelly R . Regulation of cytokine-inducible nitric oxide synthase in cardiac myocytes and microvascular endothelial cells. Role of extracellular signal-regulated kinases 1 and 2 (ERK1/ERK2) and STAT1 alpha. J Biol Chem. 1996; 271(2):1111-7. DOI: 10.1074/jbc.271.2.1111. View

19.

Pestka S, Langer J, Zoon K, Samuel C . Interferons and their actions. Annu Rev Biochem. 1987; 56:727-77. DOI: 10.1146/annurev.bi.56.070187.003455. View

20.

Yoshimoto T, Okamura H, Tagawa Y, Iwakura Y, Nakanishi K . Interleukin 18 together with interleukin 12 inhibits IgE production by induction of interferon-gamma production from activated B cells. Proc Natl Acad Sci U S A. 1997; 94(8):3948-53. PMC: 20548. DOI: 10.1073/pnas.94.8.3948. View