CD4+ヘルパーT細胞分化の基礎と臨床
抗原特異性を持つCD4+ヘルパーT細胞（Th細胞）は，獲得免疫機構において中心的な役割を担っている．Th細胞は胸腺で教育・選択を受けた後，末梢組織に分布し，抗原提示細胞による刺激を受けると，周囲のサイトカイン環境や副刺激の種類により，IFN-γを主に産生するTh1細胞，IL-4, 5, 13を主に産生するTh2細胞，あるいはIL-17を主に産生するTh17細胞という少なくとも3種類の異なるエフェクター細胞へと分化し，それぞれ細胞性免疫，液性免疫，炎症免疫機構を担っている．Th1分化にはIL-12, STAT4, T-betシグナルが，Th2分化にはIL-4, STAT6, GATA3シグナルが...
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| Published in | 日本臨床免疫学会会誌 Vol. 30; no. 6; pp. 419 - 427 |
|---|---|
| Main Author | |
| Format | Journal Article |
| Language | Japanese |
| Published |
日本臨床免疫学会
2007
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| Online Access | Get full text |
| ISSN | 0911-4300 1349-7413 |
| DOI | 10.2177/jsci.30.419 |
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| Abstract | 抗原特異性を持つCD4+ヘルパーT細胞（Th細胞）は，獲得免疫機構において中心的な役割を担っている．Th細胞は胸腺で教育・選択を受けた後，末梢組織に分布し，抗原提示細胞による刺激を受けると，周囲のサイトカイン環境や副刺激の種類により，IFN-γを主に産生するTh1細胞，IL-4, 5, 13を主に産生するTh2細胞，あるいはIL-17を主に産生するTh17細胞という少なくとも3種類の異なるエフェクター細胞へと分化し，それぞれ細胞性免疫，液性免疫，炎症免疫機構を担っている．Th1分化にはIL-12, STAT4, T-betシグナルが，Th2分化にはIL-4, STAT6, GATA3シグナルが，そしてTh17分化にはIL-1β, TGF-β, IL-6, IL-23, STAT3, RORγtシグナルが重要である．特に最近その概念が確立され，独立したエフェクターCD4+ T細胞であるTh17細胞の解析により，これまでのTh1-Th2パラダイムだけでは説明できなかった多くの炎症病態が説明可能になってきている．今後は，このIL-17制御を目的にとした新たな薬剤開発が活発となるであろう． |
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| AbstractList | 「抄録」抗原特異性を持つCD4+ヘルパーT細胞(Th細胞)は, 獲得免疫機構において中心的な役割を担っている. Th細胞は胸腺で教育・選択を受けた後, 末梢組織に分布し, 抗原提示細胞による刺激を受けると, 周囲のサイトカイン環境や副刺激の種類により, IFN-γを主に産生するTh1細胞, IL-4, 5, 13を主に産生するTh2細胞, あるいはIL-17を主に産生するTh17細胞という少なくとも3種類の異なるエフェクター細胞へと分化し, Th2分化にはIL-4, STAT6, GATA3シグナルが, そしてTh17分化にはIL-1β, TGF-β, IL-6, IL-23, STAT3, RORγtシグナルが重要である. 特に最近その概念が確立され, 独立したエフェクターDC4+T細胞であるTh17細胞の解析により, これまでのTh1-Th2パラダイムだけでは説明できなかった多くの炎症病態が説明可能になってきている. 今後は, このIL-17制御を目的にとした新たな薬剤開発が活発となるであろう. 「はじめに」昆虫から存在する自然免疫に対して高等生物にしか存在しない獲得免疫機構において, 中心的な役割を担っているのが抗原特異性を持つCD4+ヘルパーT細胞(Th細胞)である. 抗原特異性を持つCD4+ヘルパーT細胞（Th細胞）は，獲得免疫機構において中心的な役割を担っている．Th細胞は胸腺で教育・選択を受けた後，末梢組織に分布し，抗原提示細胞による刺激を受けると，周囲のサイトカイン環境や副刺激の種類により，IFN-γを主に産生するTh1細胞，IL-4, 5, 13を主に産生するTh2細胞，あるいはIL-17を主に産生するTh17細胞という少なくとも3種類の異なるエフェクター細胞へと分化し，それぞれ細胞性免疫，液性免疫，炎症免疫機構を担っている．Th1分化にはIL-12, STAT4, T-betシグナルが，Th2分化にはIL-4, STAT6, GATA3シグナルが，そしてTh17分化にはIL-1β, TGF-β, IL-6, IL-23, STAT3, RORγtシグナルが重要である．特に最近その概念が確立され，独立したエフェクターCD4+ T細胞であるTh17細胞の解析により，これまでのTh1-Th2パラダイムだけでは説明できなかった多くの炎症病態が説明可能になってきている．今後は，このIL-17制御を目的にとした新たな薬剤開発が活発となるであろう． |
| Author | 臼井, 崇 |
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| Copyright | 2007 日本臨床免疫学会 |
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| References | 6) Harrington LE, Hatton RD, Mangan PR, et al. : Interleukin 17-producing CD4+ effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages. Nat Immunol 6 : 1123-1132, 2005. 51) Fang TC, Yashiro-Ohtani Y, Del Bianco C, Knoblock DM, Blacklow SC, Pear WS. : Notch directly regulates Gata3 expression during T helper 2 cell differentiation. Immunity 27 : 100-110, 2007. 45) Weaver CT, Hatton RD, Mangan PR, Harrington LE. : IL-17 Family Cytokines and the Expanding Diversity of Effector T Cell Lineages. Annu Rev Immunol 25 : 821-852, 2007. 25) Yang J, Murphy TL, Ouyang W, Murphy KM. : Induction of interferon-gamma production in Th1 CD4+ T cells: evidence for two distinct pathways for promoter activation. Eur J Immunol 29 : 548-555, 1999. 12) Holzer U, Kwok WW, Nepom GT, Buckner JH. : Differential antigen sensitivity and costimulatory requirements in human Th1 and Th2 antigen-specific CD4+ cells with similar TCR avidity. 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J Immunol 136 : 2348-2357, 1986. 7) Park H, Li Z, Yang XO, et al. : A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17. Nat Immunol 6 : 1133-1141, 2005. 29) Lighvani AA, Frucht DM, Jankovic D, et al. : T-bet is rapidly induced by interferon-gamma in lymphoid and myeloid cells. Proc Natl Acad Sci U S A 98 : 15137-15142, 2001. 27) Szabo SJ, Sullivan BM, Stemmann C, Satoskar AR, Sleckman BP, Glimcher LH. : Distinct effects of T-bet in TH1 lineage commitment and IFN-gamma production in CD4 and CD8 T cells. Science 295 : 338-342, 2002. 39) Rengarajan J, Tang B, Glimcher LH. : NFATc2 and NFATc3 regulate T(H)2 differentiation and modulate TCR-responsiveness of naive T(H)cells. Nat Immunol 3 : 48-54, 2002. 46) Laurence A, Tato CM, Davidson TS, et al. : Interleukin-2 signaling via STAT5 constrains T helper 17 cell generation. 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Nat Immunol 3 : 549-557, 2002. 13) Marsland BJ, Soos TJ, Spath G, Littman DR, Kopf M. : Protein kinase C theta is critical for the development of in vivo T helper (Th)2 cell but not Th1 cell responses. J Exp Med 200 : 181-189, 2004. |
| References_xml | – reference: 11) Afzali B, Lombardi G, Lechler RI, Lord GM. : The role of T helper 17 (Th17) and regulatory T cells (Treg) in human organ transplantation and autoimmune disease. Clin Exp Immunol 148 : 32-46, 2007. – reference: 44) Gutcher I, Becher B. : APC-derived cytokines and T cell polarization in autoimmune inflammation. J Clin Invest 117 : 1119-1127, 2007. – reference: 2) Murphy KM, Reiner SL. : The lineage decisions of helper T cells. Nat Rev Immunol 2 : 933-944, 2002. – reference: 12) Holzer U, Kwok WW, Nepom GT, Buckner JH. : Differential antigen sensitivity and costimulatory requirements in human Th1 and Th2 antigen-specific CD4+ cells with similar TCR avidity. J Immunol 170 : 1218-1223, 2003. – reference: 13) Marsland BJ, Soos TJ, Spath G, Littman DR, Kopf M. : Protein kinase C theta is critical for the development of in vivo T helper (Th)2 cell but not Th1 cell responses. J Exp Med 200 : 181-189, 2004. – reference: 45) Weaver CT, Hatton RD, Mangan PR, Harrington LE. : IL-17 Family Cytokines and the Expanding Diversity of Effector T Cell Lineages. Annu Rev Immunol 25 : 821-852, 2007. – reference: 7) Park H, Li Z, Yang XO, et al. : A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17. Nat Immunol 6 : 1133-1141, 2005. – reference: 21) Grogan JL, Mohrs M, Harmon B, Lacy DA, Sedat JW, Locksley RM. : Early transcription and silencing of cytokine genes underlie polarization of T helper cell subsets. Immunity 14 : 205-215, 2001. – reference: 30) Usui T, Preiss JC, Kanno Y, et al. : T-bet regulates Th1 responses through essential effects on GATA3 function rather than on IFNG gene acetylation and transcription. J Exp Med 203 : 755-766, 2006. – reference: 10) Stockinger B, Veldhoen M. : Differentiation and function of Th17 T cells. Curr Opin Immunol 2007. – reference: 39) Rengarajan J, Tang B, Glimcher LH. : NFATc2 and NFATc3 regulate T(H)2 differentiation and modulate TCR-responsiveness of naive T(H)cells. Nat Immunol 3 : 48-54, 2002. – reference: 6) Harrington LE, Hatton RD, Mangan PR, et al. : Interleukin 17-producing CD4+ effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages. Nat Immunol 6 : 1123-1132, 2005. – reference: 28) Afkarian M, Sedy JR, Yang J, et al. : T-bet is a STAT1-induced regulator of IL-12R expression in naive CD4(+) T cells. Nat Immunol 3 : 549-557, 2002. – reference: 51) Fang TC, Yashiro-Ohtani Y, Del Bianco C, Knoblock DM, Blacklow SC, Pear WS. : Notch directly regulates Gata3 expression during T helper 2 cell differentiation. Immunity 27 : 100-110, 2007. – reference: 1) Mosmann TR, Cherwinski H, Bond MW, Giedlin MA, Coffman RL : Two types of murine helper T cell clone. I. Definition according to profiles of lymphokine activities and secreted proteins. J Immunol 136 : 2348-2357, 1986. – reference: 41) Das J, Chen CH, Yang L, Cohn L, Ray P, Ray A. : A critical role for NF-kappa B in GATA3 expression and TH2 differentiation in allergic airway inflammation. Nat Immunol 2 : 45-50, 2001. – reference: 35) Miaw SC, Choi A, Yu E, Kishikawa H, Ho IC. : ROG, repressor of GATA, regulates the expression of cytokine genes. Immunity 12 : 323-333, 2000. – reference: 50) Amsen D, Antov A, Jankovic D, et al. : Direct regulation of Gata3 expression determines the T helper differentiation potential of Notch. Immunity 27 : 89-99, 2007. – reference: 26) Yang J, Zhu H, Murphy TL, Ouyang W, Murphy KM. : IL-18-stimulated GADD45 beta required in cytokine-induced, but not TCR-induced, IFN-gamma production. Nat Immunol 2 : 157-164, 2001. – reference: 5) Roncarolo MG, Bacchetta R, Bordignon C, Narula S, Levings MK. : Type 1 T regulatory cells. Immunol Rev 182 : 68-79, 2001. – reference: 9) Liew FY. : T(H)1 and T(H)2 cells: a historical perspective. Nat Rev Immunol 2 : 55-60, 2002. – reference: 37) Lohoff M, Duncan GS, Ferrick D, et al. : Deficiency in the transcription factor interferon regulatory factor (IRF)-2 leads to severely compromised development of natural killer and T helper type 1 cells. J Exp Med 192 : 325-336, 2000. – reference: 34) Zhou M, Ouyang W, Gong Q, et al. : Friend of GATA-1 represses GATA3-dependent activity in CD4+ T cells. J Exp Med 194 : 1461-1471, 2001. – reference: 53) Neurath MF. : IL-23: a master regulator in Crohn disease. Nat Med 13 : 26-28, 2007. – reference: 33) Komine O, Hayashi K, Natsume W, et al. : The Runx1 transcription factor inhibits the differentiation of naive CD4+ T cells into the Th2 lineage by repressing GATA3 expression. J Exp Med 198 : 51-61, 2003. – reference: 36) Lohoff M, Ferrick D, Mittrucker HW, et al. : Interferon regulatory factor-1 is required for a T helper 1 immune response in vivo. Immunity 6 : 681-689, 1997. – reference: 43) Yang XO, Panopoulos AD, Nurieva R, et al. : STAT3 regulates cytokine-mediated generation of inflammatory helper T cells. J Biol Chem 282 : 9358-9363, 2007. – reference: 48) Batten M, Li J, Yi S, et al. : Interleukin 27 limits autoimmune encephalomyelitis by suppressing the development of interleukin 17-producing T cells. Nat Immunol 7 : 929-936, 2006. – reference: 16) Gorelik L, Constant S, Flavell RA. : Mechanism of Transforming Growth Factor beta-induced Inhibition of T Helper Type 1 Differentiation. J Exp Med 195 : 1499-1505, 2002. – reference: 18) Khader SA, Pearl JE, Sakamoto K, et al. : IL-23 compensates for the absence of IL-12p70 and is essential for the IL-17 response during tuberculosis but is dispensable for protection and antigen-specific IFN-gamma responses if IL-12p70 is available. 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| Snippet | 抗原特異性を持つCD4+ヘルパーT細胞（Th細胞）は，獲得免疫機構において中心的な役割を担っている．Th細胞は胸腺で教育・選択を受けた後，末梢組織に分布し，抗原提示細... 「抄録」抗原特異性を持つCD4+ヘルパーT細胞(Th細胞)は, 獲得免疫機構において中心的な役割を担っている. Th細胞は胸腺で教育・選択を受けた後, 末梢組織に分布し, 抗原提示... |
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| Title | CD4+ヘルパーT細胞分化の基礎と臨床 |
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