1994 Fiscal Year Annual Research Report

IL-2受容体γ鎖変異による伴性重症複合免疫不全症の発症機構に関する研究

Research Project

Project/Area Number	06404025
Research Category	Grant-in-Aid for General Scientific Research (A)
Research Institution	Tohoku University
Principal Investigator	菅村和夫東北大学, 医学部, 教授 (20117360)
Co-Investigator(Kenkyū-buntansha)	今野多助東北大学, 加齢医学研究所, 教授 (00004846) 大保和之東北大学, 医学部, 助手 (70250751) 浅尾裕信東北大学, 医学部, 助手 (80250744)
Keywords	IL-2 / IL-2受容体 / γ鎖 / XSCID / JAK1,3 / シグナル伝達
Research Abstract	X連鎖重症複合免疫不全症(XSCID)の原因遺伝子であるγ鎖の機能を、XSCID患者由来の変異γ鎖と、γ鎖のノックアウトマウスを用いて解析した。3名のXSCID患者由来のγ鎖の変異は、細胞質外領域に点変異がありIL-2が結合しなくなったもの、細胞質内に欠失がありSH2様領域の一部を欠きIL-2は結合できるがシグナル伝達ができなくなったもの、γ鎖の第2エクソンが欠失しγ鎖蛋白の発現がないものであった。これらの患者由来のγ鎖のDNAをヒトT細胞株ED40515(-)に導入して機能を解析したところ、正常γ鎖を導入した細胞株ではIL-2による細胞増殖がみられたのに対し、変異γ鎖導入細胞株では増殖は認められなかった。従って、XSCIDの発症はγ鎖の機能の異常に伴うT細胞の分化不全によるのと推定される。γ鎖はIL-2ばかりでなくIL-4、IL-7、IL-9、IL-15の受容体のサブユニットになっている。マウス胸腺の器官培養系で、ダブルネガティブ(CD4^-CD8^-)細胞の内で、最も未熟と考えられているPgp-1^+,c-kit^+細胞を培養すると、9日目には多くのダブルポジティブ(CD4^+CD8^+)細胞が出現する。そこに抗γ鎖抗体(TUGm2)と抗IL-7受容体抗体(A7R34)を加えると、この分化は完全に阻止された。このことは、IL-7が胸腺T細胞の分化に必須であり、そこにγ鎖が要求されることを示している。γ鎖を欠失したマウスの作出に成功した。γ鎖の細胞内領域を相同組み換えにより欠いたES細胞から、γ鎖変異マウスは正常に発生し、生育した。しかし、胸腺は萎縮しており、末梢のT細胞・B細胞ともに著しく減少していた。B細胞の減少はヒトXSCIDの表現型と異なる。今後、このγ鎖欠失マウスを詳細に解析し、動物モデルとしての確立を目指す。

Research Products

(17 results)

All Other

All Publications (17 results)

[Publications] Kondo,M.: "Functional participation of the IL-2 receptor γ chain in IL-7 receptor complexes." Science. 263. 1453-1454 (1994)
[Publications] Roessler,E.: "Cooperative interactions between the interleukin 2 recepotr α and β chains alter the interleukin 2-binding affinity of the receptor subunits." Proc.Natl.Acad.Sci.USA. 91. 3344-3347 (1994)
[Publications] Vanham,G.: "The interleukin-2 receptor subunit expression and function on peripheral blood lymphocytes from HIV-infected and control persons." Clin.Immunol.Immunopathol.71. 60-68 (1994)
[Publications] Ishii,N.: "Impairment of ligand binding and growth signaling of mutant IL-2 receptor γ chains in patients with X-liked severe combined immunodeficiency." J.Immunol.153. 1310-1317 (1994)
[Publications] Tanaka,N.: "Physical association of JAK1 and JAK2 tyrosine kinases with the interleukin 2 receptor β and γ chains." Proc.Natl.Acad.Sci.USA. 91. 7271-7275 (1994)
[Publications] Ishii,N.: "Expression of the interleukin 2 receptor γ chain on various populations in human peripheral blood." Inter.Immunol.6. 1273-1277 (1994)
[Publications] Asao,H.: "Interleukin 2-induced activation of JAK3:possible involvement in signal transduction for c-myc induction and cell proliferation." FEBS Letters. 351. 201-206 (1994)
[Publications] Kondo,M.: "Expression of the mouse interleukin-2 receptor γ chain in various cell populations of thymus and spleen." Eur.J.Immunol.24. 2026-2030 (1994)
[Publications] Hozumi,K.: "Implication of the common γ chain of the IL-7 receptor in intrathymic development of pro-T cells." Inter.Immunol.6. 1451-1454 (1994)
[Publications] Yaegashi,N.: "The frequency of human parvovirus B19 infection in nonimmune hydrops fetalis." J.Perinatal Medicine.22. 159-163 (1994)
[Publications] Asano,M.: "Interleukin-2 can support growth of CD8_+T cells but not CD4_+T cells of human IL-2 receptor β chain transgeneic mice." J.Immunol.153. 5373-5381 (1994)
[Publications] Bosco,M.C.: "Regulation by interleukin-2(IL-2)and interferon γ of of IL-2 receptor γ chain gene expression in human monocytes." Blood. 83. 2995-3002 (1994)
[Publications] Minegishi,Y.: "Preferential utilization of immature JH segment and absence of somatic mutation in CDR3 junction of Ig H chain gene in three X-linked severe combined immunodeficiency patients." Inter.Immunol.(in press).
[Publications] Kimura,Y.: "Sharing of the IL-2 receptor γ chain with the functional IL-9 receptor complex." Inter.Immunol.(in press).
[Publications] Watanabe,S.: "Involvement of the IL-2 receptor γ subunit in IL-4-dependent activation of mouse hematopoietic cells and splenic B cells." Eur.J.Immunol.(in press).
[Publications] Ohbo,K.: "Functional analysis of the human interleukin 2 receptor γ chain gene promoter." J.Biol.Chem. (in press).
[Publications] Sugamura,K.: "The common γ chain for multiple cytokine receptors." Adv.Immunol.(in press).

1994 Fiscal Year Annual Research Report

IL-2受容体γ鎖変異による伴性重症複合免疫不全症の発症機構に関する研究

Principal Investigator

菅村 和夫 東北大学, 医学部, 教授 (20117360)

Research Products

[Publications] Kondo,M.: "Functional participation of the IL-2 receptor γ chain in IL-7 receptor complexes." Science. 263. 1453-1454 (1994)

[Publications] Roessler,E.: "Cooperative interactions between the interleukin 2 recepotr α and β chains alter the interleukin 2-binding affinity of the receptor subunits." Proc.Natl.Acad.Sci.USA. 91. 3344-3347 (1994)

[Publications] Vanham,G.: "The interleukin-2 receptor subunit expression and function on peripheral blood lymphocytes from HIV-infected and control persons." Clin.Immunol.Immunopathol.71. 60-68 (1994)

[Publications] Ishii,N.: "Impairment of ligand binding and growth signaling of mutant IL-2 receptor γ chains in patients with X-liked severe combined immunodeficiency." J.Immunol.153. 1310-1317 (1994)

[Publications] Tanaka,N.: "Physical association of JAK1 and JAK2 tyrosine kinases with the interleukin 2 receptor β and γ chains." Proc.Natl.Acad.Sci.USA. 91. 7271-7275 (1994)

[Publications] Ishii,N.: "Expression of the interleukin 2 receptor γ chain on various populations in human peripheral blood." Inter.Immunol.6. 1273-1277 (1994)

[Publications] Asao,H.: "Interleukin 2-induced activation of JAK3:possible involvement in signal transduction for c-myc induction and cell proliferation." FEBS Letters. 351. 201-206 (1994)

[Publications] Kondo,M.: "Expression of the mouse interleukin-2 receptor γ chain in various cell populations of thymus and spleen." Eur.J.Immunol.24. 2026-2030 (1994)

[Publications] Hozumi,K.: "Implication of the common γ chain of the IL-7 receptor in intrathymic development of pro-T cells." Inter.Immunol.6. 1451-1454 (1994)

[Publications] Yaegashi,N.: "The frequency of human parvovirus B19 infection in nonimmune hydrops fetalis." J.Perinatal Medicine.22. 159-163 (1994)

[Publications] Asano,M.: "Interleukin-2 can support growth of CD8_+T cells but not CD4_+T cells of human IL-2 receptor β chain transgeneic mice." J.Immunol.153. 5373-5381 (1994)

[Publications] Bosco,M.C.: "Regulation by interleukin-2(IL-2)and interferon γ of of IL-2 receptor γ chain gene expression in human monocytes." Blood. 83. 2995-3002 (1994)

[Publications] Minegishi,Y.: "Preferential utilization of immature JH segment and absence of somatic mutation in CDR3 junction of Ig H chain gene in three X-linked severe combined immunodeficiency patients." Inter.Immunol.(in press).

[Publications] Kimura,Y.: "Sharing of the IL-2 receptor γ chain with the functional IL-9 receptor complex." Inter.Immunol.(in press).

[Publications] Watanabe,S.: "Involvement of the IL-2 receptor γ subunit in IL-4-dependent activation of mouse hematopoietic cells and splenic B cells." Eur.J.Immunol.(in press).

[Publications] Ohbo,K.: "Functional analysis of the human interleukin 2 receptor γ chain gene promoter." J.Biol.Chem. (in press).

[Publications] Sugamura,K.: "The common γ chain for multiple cytokine receptors." Adv.Immunol.(in press).

菅村和夫東北大学, 医学部, 教授 (20117360)