跳到主要內容

臺灣博碩士論文加值系統

(216.73.216.88) 您好!臺灣時間:2026/02/15 08:41
字體大小: 字級放大   字級縮小   預設字形  
回查詢結果 :::

詳目顯示

我願授權國圖
: 
twitterline
研究生:郭沛羽
研究生(外文):Pei-Yu Kuo
論文名稱:RestingCD4+及CD8+T淋巴球之IL-4接受器的功能特性
論文名稱(外文):Distinct Functional Role of IL-4 Receptor on Resting CD4+ and CD8+ T Cells
指導教授:孔祥智孔祥智引用關係
指導教授(外文):John T. Kung
學位類別:碩士
校院名稱:國立臺灣大學
系所名稱:免疫學研究所
學門:醫藥衛生學門
學類:醫學學類
論文種類:學術論文
論文出版年:1999
畢業學年度:87
語文別:英文
論文頁數:51
中文關鍵詞:IL-4CD4+ T 細胞CD8+ T細胞Stat6IL-4IL-2
外文關鍵詞:IL-4CD4+ T cellsCD8+ T cellsStat6IL-4RIL-2
相關次數:
  • 被引用被引用:0
  • 點閱點閱:366
  • 評分評分:
  • 下載下載:0
  • 收藏至我的研究室書目清單書目收藏:0
細胞激素IL-4在免疫反應的調控及分化上扮演了舉足輕重的角色,其中IL-4最為人熟知的功用在於1) 其可引導活化中的T細胞分化成可分泌第二型細胞激素之effector 細胞及 2) 做為B細胞的生長激素之功能。儘管 IL-4有這許多為人熟知的作用,但關於IL-4作用在resting T細胞的功用仍有待瞭解。在這篇論文中,我們發現以IL-4培養過的resting CD8+ T細胞具有1) 細胞表面CD8分子的表現增加及2) 在面對無論是mitogen或是抗原的刺激時,這些細胞皆能有較高的proliferation及IL-2 production。然而,以IL-4培養對於CD4+ T細胞卻有相反的影響。以IL-4培養resting CD4+ T細胞,不但會降低其細胞表面的CD4分子表現,對於活化的刺激更有降低proliferation及IL-2 production的反應。此外,利用Stat6-null老鼠的T細胞,我們發現上述這種IL-4降低CD4+ T細胞CD4表現及活化反應是需要有Stat6 分子的作用,但缺乏Stat6的存在卻不會影響到IL-4培養所達成增強CD8+ T細胞功能。
歸納上述結果,我們報告IL-4培養會對CD4+及CD8+ T細胞造成不同且相反的作用,而這說明了同樣的IL-4R卻能在不同的T細胞傳導執行功能上產生完全相反的作用。

IL-4 is a pleiotropic cytokine which plays an important role in the immune system. The best known function of IL-4 are its ability to 1) drive antigen-activated T cells into Th2 (Tc2)-cytokine secreting effector cells and 2) serve as B cell growth factors. The effect of IL-4 on resting T cells which are known to express IL-4R has not been extensively studied. We report here that IL-4 pretreatment of resting CD8+ T cells 1) upregulated CD8 expression and 2) enhanced antigen and mitogen-induced proliferation and IL-2 production responses. On the other hand, IL-4 pretreatment of resting CD4+ T cells 1) mediated enhancement of immune functions of CD8+ T cells. Taken together, IL-4 pretreatment of resting CD4+ T cells versus CD8+ T cells resulted in differential and opposite effects and suggests that the same IL-4R can mediate functionally distinct/opposite effects on different lineage of downregulated CD4 expression and 2) decreased proliferation and IL-2 production responses. While functional Stat6 molecule was required for IL-4-mediated downregulation of CD4 expression and function by CD4+ T cells, its absence had no effect on IL-4-T cells.

Abbreviation I
Content Table II
Abstract III
Chinese Abstract (中文摘要) IV
Section I Introduction 1
Section IIMaterials and methods
1.Mice 6
2.Isolation of spleen CD4+/CD8+ T cells by
adherence to antibody-coated tissue culture plate 7
3. Analysis of cell surface marker by flow cytometry 9
4.Preparation of CD40L-transfected L cell-
activated B cell blasts as APC 10
5.IL-4 pretreatment of T cells 11
6.T cell activation 11
7.IL-2 bioassay 14
Section IIIResults 16
Section IVDiscussion 24
Section VFigures 32
Section VIReferences 43

1. Howard M. Farrar J. Hilfiker M. Johnson B. Takatsu K. Haemaoka T. Paul WE. 1982. Identification of a T-cell derived B-cell growth factor distinct from interleukin 2. J. Exp. Med. 155:914
2. Lee F. Yokota T. Otsuka T. Meyerson P. Villaret D. Coffman R. Mosmann T. Rennick D. Roehm N. Smith C. Zlotnick A. and Arai K. 1986. Isolation and characterization of a mouse interleukin cDNA clone that express B-cell stimulatory factor 1 activities and T-cell and mast-cell-stimulating activities. Proc. Natl. Acad. Sci. USA 83:2061
3. Noma Y. Sideras T. Naito T. Bergstedt-Lindqvist S. Azuma C. Severinson E. Tanabe T. Kinashi T. Matsuda F. Yaoita T. Honjo T. 1986. Cloning of the cDNA encoding the murine IgG1 induction factor by a novel strategy using SP6 promoter. Nature 319:640.
4. Paul WE. 1991. Interleukin-4: a prototypic immunoregulatory lymphokine. Blood 77:1859
5. Keegan A. D. Zamoran J. 1998. Regulation of gene expression, growth, and cell survival by IL-4: contribution of multiple signaling pathways. Cell Research 8:1.
6. Ohara J. Paul WE. 1987. Receptors for B-cell stimulatory factor-1 expressed on cells of haematopoietic lineage. Nature 325:537.
7. Park LS. Friend D. Grabstein K. Urdal DL. 1987. Characterization of the high affinity cell-surface receptor for murine B-cell-stimulating factor 1. Proc. Natl. Acad. Sci. USA 84:1669
8. Kurt-Jones EA. Hamberg S. Ohara J. Paul WE. and Abbas AK. 1987. Heterogeneity of helper / inducer T lymphocyte. I. Lymphokine production and lymphokine responsiveness. J. Exp. Med. 166:1774.
9. Greenbaum LA. Horowitz JB. Woods A. Pasqualini T. Reich EP. Bottomly K. 1988. Autocrine growth of CD4+ T cells. Differential effect of IL-1 on helper and inflammatory T cells. J. Immunol. 140:1555.
10. Mosmann TR. Bond MW. Coffman RL. Ohara J. Paul WE. 1986. T cell and mast cell line respond to B cell stimulatory factor —1. Proc. Natl. Acad. Sci. USA 83:5654.
11. Vella A. Teage TK. Ihles J. Kappler J. and Marrack P. 1997. IL-4 or IL-7 prevents the death of resting T cells: STAT6 is probably not required for the effect of IL-4. J. Exp. Med. 186:325
12. Peschel C. Paul WE. Ohara J. Green I. 1987. Effect of B-cell stimulatory factory-1/ interleukin-4 on haematopoietic progenitor cells. Blood 70:254.
13. Noelle R. Krammer PH. Ohara J. Uhr JW. Vitetta ES. 1984. Increased expression of Ia antigens on resting B cells: an additional role for B cell growth factor. Proc. Natl. Acad. Sci. USA 81:6149.
14. Hudak SA. Gollnick SO. Conrad DH. and Kehry MR. 1987. Murine B-cell stimulatory factor 1 (interleukin-4) increases expression of the Fc receptor for IgE on mouse B cells. Proc. Natl. Acad. Sci. USA 84: 4606.
15. Conrad DH. Waldschmidt TJ. Lee WT. Rao M. Keegan AD. Noelle RJ. Lynch RG. and Kehry M. 1987. Effect of B cell stimulatory factor-1 (interleukin-4) on Fc and Fc receptor expression on murine B lymphocytes and B cell lines. J. Immunol. 139:2290
16. Ohara J. Paul WE. 1988. Up-regulation of interleukine-4/B- cell stimulatory factor-1 receptor expression. Proc. Natl. Acad. Sci. USA 85:8221.
17. Vitetta ES. Ohara J. Myers C. Layton J. Krammer PH. Paul WE. 1985. Serologic biochemical and functional identity of B cell stimulatory factor0-1 and B cell differentiation factor for IgG1. J. Exp. Med. 162:1726.
18. Coffman RL. Ohara J. Bond MW. Carty J. Zloynick A. Paul WE. 1986. B cell stimulatory factor-1 enhances the IgE response of lipopolysaccharide-activated B cells. J. Immunol. 136:4538.
19. Swain SL. Weinberg AD. English M. Huston G. 1990. IL-4 directs the development of Th-2-like helper effectors. J. Immunol. 145:3796.
20. LeGros GG. Ben-Sasson SS. Seder R. Finkelman FD. Paul WE. 1990. Generation of interleukin-4 (IL-4)-producing cell in vivo and in vitro: IL-2 and IL-4 are required for in vitro generation of IL-4-producing cells. J. Exp. Med. 172:921.
21. Hsieh CS. Heimberger AB. Gold JS. O’Garra A. Murphy KM. 1992. Differential regulation of T helper phenotype development by interleukin-4 and 10 in an alpha beta T cell-receptor transgenic system. Proc. Natl. Acad. Sci. USA 89:6065.
22. Seder RA. Paul WE. Davis MM. Fazekas DS. Groth B. 1992. The presence of interleukin-4 during in vitro priming determines the lymphokine-producing potential of CD4+ T cells from T cell receptor transgenic mice. J. Exp. Med. 176:1091.
23. Ruppert J. Friedrichs D. Xu H. Peters JH. 1991. IL-4 decreases the expression of monocyte differentiation marker CD14, paralleled by an increasing accessory potency. Immunobiology. 182(5):449.
24. Golumbek PT. Lazenby AJ. Levitsky HI. Jaffee LM. Karasuyama H. Baker M. Pardoll DM. 1991. Treatment of established renal cancer by tumor cells engineered to secret interleukin-4. Science 254:713.
25. Tepper RI. Coffman RL. Leder P. 1992. An eosinophil-dependent mechanism for the anti-tumor effect of interleukin-4. Science 257:548.
26. Toi M. Bicknall R. Harris AL. 1992. Inhibition of colon and breast carcinoma cell growth by interleukin-4. Cancer Res. 52:275.
27. Doucet C. Brouty-Boye D. Pottin-Clemenceau C. Jasmin C. Canonica GW. Azzarone B. 1998. IL-4 and IL13 specially increase adhesion molecule and inflammatory cytokine expression in human lung fibroblasts. Int. Immunol. 10:1421.
28. Swerlick RA. Lee KH. Li LJ. Sepp NT. Caughman SW. Lawley TJ. 1992. Regulation of vascular adhesion molecule 1 on human dermal microvascular endothelial cells. J. Immunol. 149:698.
29. Schleimer RP. Sterbinsky SA. Kaiser J. Bickel CA. Klunk DA. Tomioka K. Newman W. Luscinskas FW. Gimbrone MA. McIntyre BW. And Bochner BS. 1992. IL-4 induces adherence of human eosinophils and basophils but not neutrophils to endotheliam. Association with expression of VCAM-1. J. Immunol. 148:1086.
30. Zund G. Madara JL. Awtrey CS. Colgan SP. 1996. Interleukin-4 and interleukin-13 differentially regulate epithelial chloride secretion. J. Biol. Chem. 271: 7460.
31. Mosley B. Beckmann MP. March CJ. 1989. The murine IL-4 receptor: molecular cloning and characterization of secreted and membrane bound form. Cell 59: 335.
32. Harada N. Castle BE. Gorman DM. 1990. Expression cloning of a cDNA encoding the murine IL-4 receptor based on ligand binding. Proc. Natl. Acad. Sci. USA 87:857.
33. Idzerda RL. March CJ. Mosley B. 1990. Human IL-4 receptor confers biological responsiveness and defines a novel receptor superfamily. J. Exp. Med. 171:861.
34. Galizzi JP. Zuber CE. Harada N. 1990. Molecular cloning of a cDNA encoding the human IL-4 receptor. Int. Immunol. 2:669.
35. Kondo M. Takeshita T. Ishii N. Nakamura M. Watanabe S. Arai K. Sugamura K. 1993. Sharing of the interleukin-2 (IL-2) receptor  chain between receptors for IL-2 and IL-4. Science 262:1874.
36. Russel SM. Keegan AD. Harada N. Nakamura Y. Noguchi M. Leland P. Friedmann MC. Miyajima A. Puri RK. Paul WE. Leonard WJ. 1993. The interleukin 2 receptor  chain is a functional component of the interleukin 4 receptor. Science 262:1880.
37. Callard RE. Matthews DJ. Hibbert L. IL-4 and IL-13 receptors: are they one and the same? Immunol. Today 17:108.
38. Hilton DJ. Zhang J-G. Metcalf D. Alexander WS. Nicola NA. Willson TA. 1996. Cloning and characterization of a binding subunit of the IL-13 receptor that is also a component of the IL-4 receptor. Proc. Natl. Acad. Sci. USA 93: 497.
39. Aman AJ. Tayebi N. Obiri NI. Puri RK. Modi WS. Leonard WJ. cDNA cloning and characterization of the human interkeukin 13 receptor alpha chain. J. Bio. Chem. 271: 29265.
40. Caput D. Laurent P. Kaghed M. Lelias J-M. Lefort S. Vito N. Ferrere P. Cloning and characterization of a specific IL-13 binding protein structurally related to the IL-5 receptor alpha chain. J. Biol. Chem. 271: 16921.
41. Lowenthal JW. Castle BE. Christiansen J. Schreurs J. Rennick D. Arai N. Hoy P. Takebe Y. and Howard M. 1988. Expression of high affinity receptors for murine interleukin 4 (BSF-1) on hemopoietic and nonhemopoietic cells. J. Immunol. 140:456.
42. Kuhn R. Rajewsky K. Muller W. 1991. Generation and analysis of interleukin-4 deficient mice. Science 254:707.
43. Uoyd TE. Yang L. Tang DN. Bennett T. Schober W. and Lewis DE. 1997. Regulation of CD28 co-stimulation in human CD8+ T cells. J. Immunol. 158:1551
44. Sha WC. Nelson CA. newberry RD. Kranz DM. Russell JH. Loh DY. 1988. Selective expression of an antigen receptor on CD8-bearing T lymphocyte in transgenic mice. Nature. 335:271
45. Schlueter CJ. Manning TC. Schodin BA. Kranz DM. 1996. A residue in the center of peptide QL9 affects binding to the Ld and the T cell receptor. J. Immunol. 157:4478.
46. Bluthmann H. Kisielow P. Uematsu Y. Malissen M. Krimpenfort P. Berns A. von Bohmer H and Steinmetz M. 1988. T-cell-specific deletion of T-cell receptor transgenes allows functional rearrangement of endogenous - and -genes. Nature. 334:156.
47. Markiewicz MA. Girao C. Opferman JT. Sun J. Hu Q. Agulnik AA. Bishop C. Thompson CB. and Ashton-Rickardt PG. 1998. Long-term T cell memory requires the surface expression of self-peptide/major histocompatibility complex molecules. Proc. Natl. Acad. Sci. USA 95:3065.
48. Kaye J. Hsu ML. Sauron ME. Jameson SC. Gascoigne NRJ. and Hedrick SM. 1989. Selective development of CD4+ T cells in transgenic mice expressing a class II MHC-restricted antigen receptor. Nature. 341:746.
49. Janeway C.A. 1992. The T cell receptor as a multicomponent signaling machine: CD4/CD8 coreceptors and CD45 in T cell activation. Annu. Rev. Immunol. 10:645.
50. Mannie M. Rosser J. and White G. 1995. Autologus Rat myelin basic protein is a partial agonist converted into a full antagonist upon blockade of CD4. J. Immunol. 154:2642.
51. Zamoysky R. 1998. CD4 and CD8: modulators of T-cell receptor recognition of antigen and of immune response? Curr. Opin. Immunol. 10:82.
52. Ihle JN. Witthuhn BA. Quelle FW. Yamamoto K. Thierfeider WE. Kreider B. and Silvennoinen O. 1994. Signaling by the cytokine receptor superfamily: JAKs and STATs. TIBS 19:222
53. Chen XH. Patel BKR. Wang LM., Frankel M. Ellmore N. Flavell RA. LaRochelle WJ. and Pierce H. 1997. Jak1 expression is required for interleukin-4-induced tyrosine phosphorylation of insulin receptor substrate and Stat6 signaling molecules. J. Biol. Chem. 272:6556.
54. Kohler I. Rieber EP. 1993. Allergy associated Iepsilon and Fcepsilon receptor II (CD23b) activated via binding of an IL-4-induced transcription factor to a novel responsive element. Eur. J. Immunol. 23:3066.
55. Kotainides H. Reich NC. 1993. Requirement of tyrosine phosphorylation for rapid activation of a DNA binding factor by IL-4. Science 262:1265.
56. Schindler C. Kashleva H. Pernis A. Pine R. Rothman P. 1994. STFIL-4: a novel IL-4-induced signal transducing factor. EMBO J. 13:1350.
57. Hou J. Schindler U. Hanzel WJ. Ho TC. Brasseur M. McKnight SL. An IL-4 induced signal transduction factor: IL-4 STAT. Science 265:1701
58. Quelle FW. Shimoda K. Thierfelder W. Fischer C. Kim A. Ruben SM. Cleveland JL. Pierce JH. Keegan AD. Nelms K. Paul WE. and Ihle JN. 1995. Cloning of murine Stat6 and human Stat6, Stat proteins that are tyrosine phosphorylated in response to IL-4 and IL-13 but are not required for mitogenesis. Mol. Cell. Biol. 15:3336.
59. Gorman SD. Sun YH. Zamoyska R. and Parnes JR. 1988. Molecular linkage of the Ly-3 and Ly-2 genes. Requirement of Ly-2 for Ly-3 surface expression. J. Immunol. 140:3646.
60. Norment AM. Salter RD. Parham P. Engelhard VH. and Littman DR. 1988. Cell-cell adhesion mediated by CD8 and MHC class I molecule. Nature 336:79.
61. Salter RD. Benjamin RJ. Wesley PK. Buxton SE. Garrett TPJ. Clayberger C. Krensky AM. Norment AM. Littman DR. and Parham P. 1990. A binding site for the T-cell co-receptor CD8 on the 3 domain of the HLA-A2. Nature 345:41.
62. Budd RC. Cerottini JC. Horvath C. Bron C. Pedrazzini T. Howe RC. and MacDonald HR. 1997. Distinction of virgin and memory T lymphocyte. J. Immunol. 138:3120.
63. Mobley JL. Rigby SM. and Dailey MO. 1994. Regulation of adhesion molecule expression by CD8 T cells in vivo. J. Immunol. 153:5443.
64. Bruno L. Kirberg J. and von Boehmer H. 1995. On the cellular basis of immunological T cell memory. Immunity. 2:37.
65. Pihlgren M. Dubois PM. Tomkowiak M. Sjogren T. and Marvel J. 1996. Resting memory CD8+ T cells are hyperreactive to antigenic challenge in vitro. J. Exp. Med. 184:2141.
66. Luqman M. and Bottomly K. 1992. Activation requirements for CD4+ T cells differing in CD45R expression. J. Immunol. 149:2300.
67. Croft M. Duncan DD. and Swain SL. 1994. Naive versus memory CD4 T cell response to antigen. J. Immunol. 152:2675.
68. Schwarz EM. Salgame P. and Bloom BR. 1993. Molecular regulation of human interleukin 2 and T-cell function by interleukin 4. Proc. Natl. Acad. Sci. USA. 90:7734.
69. Werlen G. Jacinto E. Xia Y. and Karin M. 1998. Calcineeurin preferentially synergizes with PKC- to activate JNK and IL-2 promoter in T lymphocytes. EMBO J. 17:3101.
70. Keenan C. Long A. Volkov Y. and Kelleher D. 1997. Protein kinase C isotypes theta, delta and eta in human lymphocytes: differential responses to signalling through the T-cell receptor and phorbol esters. Immunology. 90:557.
71. Matthews DJ. Clark PA. Herbert J. Morgan G. Armitago RJ. Kinnon C. Minty A. Grabstein KH. Caput D. Ferrara P. and Callard R. 1995. Function of the interleukin-2 (IL-2) receptor gamma-chain in biologic responses of x-linked severe combined immunodeficient B cells to IL-2, IL-4, IL-13, and IL-15. Blood 85:38.
72. Reichel M. Nelson BH. Greenberg PD. and Rothman PB. 1997. The IL-4 receptor -chain cytoplasmic domain is sufficient for activation of JAK1 and STAT6 and the induction of IL-4-specific gene expression. J. Immunol. 158:5860.
73. Wang LM. Keegan AD. Li W. Leinhard GE. Pacini S. Gutkind JS. Sun XJ. White MF. Araonson SA. Paul WE. and Pierce JH. 1993. Common elements in interleukin-4 and insulin signaling pathways in factor-dependent haematopoietic cells. Proc. Natl. Acad. Sci. USA 90:4032.
74. Pernis A. Witthuhn B. Keegan AD. Nelms K. Garfein E. Ihle JN. Paul WE. Pierce JH. and Rothman P. 1995. Interleukin-4 signals through two related pathways. Proc. Natl. Acad. Sci. USA 92:7971.
75. Morris SC. Coffman RL. and Finkelman FD. 1998. In vivo IL-4 responses to anti-IgD antibody are MHC class II dependent and 2-microglobulin independent and develop normally in the absence of IL-4 priming of T cells. J. Immunol. 160:3299.
76. Morris SC. Lees A. Inman J. and Finkelman FD. 1992. Role of antigen-specific T cell help in the generation of in vivo antibody responses. I. Antigen-specific T cell help is required to generate a polyclonal IgG1 response in anti-IgD antibody-injected mice. J. Immunol. 149:3836.

QRCODE
 
 
 
 
 
                                                                                                                                                                                                                                                                                                                                                                                                               
第一頁 上一頁 下一頁 最後一頁 top