• 1 襄樊學院醫(yī)學院/附屬醫(yī)院臨床檢驗部（湖北襄樊，441053）;2 武漢大學人民醫(yī)院眼科;

【摘要】　 輔助性T細胞17（T-helper type 17，Th17）是一種以分泌白介素-17（IL-17）為特征的輔助性T淋巴細胞亞型，在自身免疫性疾病中的作用逐漸得到重視。葡萄膜炎是最常見的致盲眼病，一直是眼科研究的熱點和難點。實驗性自身免疫性葡萄膜炎（experimental autoimmune uveoretinitis， EAU）是葡萄膜炎研究的成熟動物模型，有關(guān)Th17和EAU關(guān)系的研究處于起步階段，現(xiàn)就這方面的研究現(xiàn)狀進行綜述，為葡萄膜炎的免疫機制研究提供新思路。

引用本文： 龔文容,陳震,邢怡橋. 輔助性T細胞17和實驗性自身免疫性葡萄膜炎. 華西醫(yī)學, 2011, 26(2): 301-304. doi: 復制

1. 　Mosmann TR, Cherwinski H, Bond MW, et al. Two types of murine helper T cell clone. I. Definition according to profiles of lymphokine activities and secreted proteins[J]. J Immunol, 1986, 136(7): 2348-2357.
2. 　Cua DJ, Sherlock J, Chen Y, et al. Interleukin-23 rather than interleukin-12 is the critical cytokine for autoimmune inflammation of the brain[J]. Nature, 2003, 421(6924): 744-748.
3. 　Langrish CL, Chen Y, Blumenschein WM, et al. IL-23 drives a pathogenic T cell population that induces autoimmune inflammation[J]. J Exp Med, 2005, 201(2): 233-240.
4. 　Park H, Li Z, Yang XO, et al. A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17[J]. Nat Immunol, 2005, 6(11): 1133-1141.
5. 　Bettelli E, Carrier Y, Gao W, et al. Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells[J]. Nature, 2006, 441(7090): 235-238.
6. 　Korn T, Bettelli E, Gao W, et al. IL-21 initiates an alternative pathway to induce proinflammatory T(H)17 cells[J]. Nature, 2007, 448(7152): 484-487.
7. 　Yang L, Anderson DE, Baecher-Allan C, et al. IL-21 and TGF-beta are required for differentiation of human T(H)17 cells[J]. Nature, 2008, 454(7202): 350-352.
8. 　Yen D, Cheung J, Scheerens H, et al. IL-23 is essential for T cell-mediated colitis and promotes inflammation via IL-17 and IL-6[J]. J Clin Invest, 2006, 116(5): 1310-1316.
9. 　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[J]. Nat Immunol, 2005, 6(11): 1123-1132.
10. 　Aggarwal S, Ghilardi N, Xie MH, et al. Interleukin-23 promotes a distinct CD4 T cell activation state characterized by the production of interleukin-17[J]. J Biol Chem, 2003, 278(3): 1910-1914.
11. 　Chen Z, Laurence A, O’Shea JJ. Signal transduction pathways and transcriptional regulation in the control of Th17 differentiation[J]. Semin Immunol, 2007, 19(6): 400-408.
12. 　Ivanov II, McKenzie BS, Zhou L, et al. The orphan nuclear receptor RORgammat directs the differentiation program of proinflammatory IL-17+ T helper cells[J]. Cell, 2006, 126(6): 1121-1133.
13. 　Wei L, Laurence A, Elias KM, et al. IL-21 is produced by Th17 cells and drives IL-17 production in a STAT3-dependent manner[J]. J Biol Chem, 2007, 282(48): 34605-34610.
14. 　Joosten LA, Abdollahi-Roodsaz S, Heuvelmans-Jacobs M, et al. T cell dependence of chronic destructive murine arthritis induced by repeated local activation of Toll-like receptor-driven pathways: crucial role of both interleukin-1beta and interleukin-17[J]. Arthritis Rheum, 2008, 58(1): 98-108.
15. 　Mangan PR, Harrington LE, O’Quinn DB, et al. Transforming growth factor-beta induces development of the T(H)17 lineage[J]. Nature, 2006, 441(7090): 231-234.
16. 　Zhou L, Lopes JE, Chong MM, et al. TGF-beta-induced Foxp3 inhibits T(H)17 cell differentiation by antagonizing RORgammat function[J]. Nature, 2008, 453(7192): 236-240.
17. 　Niedbala W, Wei XQ, Cai B, et al. IL-35 is a novel cytokine with therapeutic effects against collagen-induced arthritis through the expansion of regulatory T cells and suppression of Th17 cells[J]. Eur J Immunol, 2007, 37(11): 3021-3029.
18. 　Batten M, Li J, Yi S, et al. Interleukin 27 limits autoimmune encephalomyelitis by suppressing the development of interleukin 17-producing T cells[J]. Nat Immunol, 2006, 7(9): 929-936.
19. 　McGeachy MJ, Bak-Jensen KS, Chen Y, et al. TGF-beta and IL-6 drive the production of IL-17 and IL-10 by T cells and restrain T(H)-17 cell-mediated pathology[J]. Nat Immunol, 2007, 8(12): 1390-1397.
20. 　Spolski R, Leonard WJ. Interleukin-21: basic biology and implications for cancer and autoimmunity[J]. Annu Rev Immunol, 2008, 26: 57-79.
21. 　Zheng Y, Danilenko DM, Valdez P, et al. Interleukin-22, a T(H)17 cytokine, mediates IL-23-induced dermal inflammation and acanthosis[J]. Nature, 2007, 445(7128): 648-651.
22. 　Caspi RR. Th1 and Th2 responses in pathogenesis and regulation of experimental autoimmune uveoretinitis[J]. Int Rev Immunol, 2002, 21(2-3): 197-208.
23. 　Amadi-Obi A, Yu CR, Liu X, et al. TH17 cells contribute to uveitis and scleritis and are expanded by IL-2 and inhibited by IL-27/STAT1[J]. Nat Med, 2007, 13(6): 711-718.
24. 　Luger D, Silver PB, Tang J, et al. Either a Th17 or a Th1 effector response can drive autoimmunity: conditions of disease induction affect dominant effector category[J]. J Exp Med, 2008, 205(4): 799-810.
25. 　Tarrant TK, Silver PB, Chan CC, et al. Endogenous IL-12 is required for induction and expression of experimental autoimmune uveitis[J]. J Immunol, 1998, 161(1): 122-127.
26. 　Yoshimura T, Sonoda KH, Ohguro N, et al. Involvement of Th17 cells and the effect of anti-IL-6 therapy in autoimmune uveitis[J]. Rheumatology (Oxford), 2009, 48(4): 347-354.
27. 　Brereton CF, Sutton CE, Lalor SJ, et al. Inhibition of ERK MAPK suppresses IL-23- and IL-1-driven IL-17 production and attenuates autoimmune disease[J]. J Immunol, 2009, 183(3): 1715-1723.
28. 　Liu X, Lee YS, Yu CR, et al. Loss of STAT3 in CD4+ T cells prevents development of experimental autoimmune diseases[J]. J Immunol, 2008, 180(9): 6070-6076.
29. 　Haak S, Croxford AL, Kreymborg K, et al. IL-17A and IL-17F do not contribute vitally to autoimmune neuro-inflammation in mice[J]. J Clin Invest, 2009, 119(1): 61-69.
30. 　Yoshimura T, Sonoda KH, Ohguro N, et al. Involvement of Th17 cells and the effect of anti-IL-6 therapy in autoimmune uveitis[J]. Rheumatology(Oxford), 2009, 48(4): 347-354.
31. 　Hohki S, Ohguro N, Haruta H, et al. Blockade of interleukin-6 signaling suppresses experimental autoimmune uveoretinitis by the inhibition of inflammatory Th17 responses[J]. Exp Eye Res, 2010, 91(2): 162-170.
32. 　Bain DL, Heneghan AF, Connaghan-Jones KD, et al. Nuclear receptor structure: implications for function[J]. Annu Rev Physiol, 2007, 69: 201-220.
33. 　Mucida D, Park Y, Kim G, et al. Reciprocal TH17 and regulatory T cell differentiation mediated by retinoic acid[J]. Science (NY), 2007, 317(5835): 256-260.
34. 　Sun CM, Hall JA, Blank RB, et al. Small intestine lamina propria dendritic cells promote de novo generation of Foxp3 T reg cells via retinoic acid[J]. J Exp Med, 2007, 204(8): 1775-1785.
35. 　Lathrop SK, Santacruz NA, Pham D, et al. Antigen-specific peripheral shaping of the natural regulatory T cell population[J]. J Exp Med, 2008, 205(13): 3105-3117.
36. 　Coombes JL, Siddiqui KR, Arancibia-Carcamo CV, et al. A functionally specialized population of mucosal CD103+ DCs induces Foxp3+ regulatory T cells via a TGF-beta and retinoic acid-dependent mechanism[J]. J Exp Med, 2007, 204(8): 1757-1764.
37. 　Elias KM, Laurence A, Davidson TS, et al. Retinoic acid inhibits Th17 polarization and enhances FoxP3 expression through a Stat-3/Stat-5 independent signaling pathway[J]. Blood, 2008, 111(3): 1013-1020.
38. 　Schambach F, Schupp M, Lazar MA, et al. Activation of retinoic acid receptor-alpha favours regulatory T cell induction at the expense of IL-17-secreting T helper cell differentiation[J]. Eur J Immuol, 2007, 37(9): 2396-2399.
39. 　Xiao S, Jin H, Korn T, et al. Retinoic acid increases Foxp3+ regulatory T cells and inhibits development of Th17 cells by enhancing TGF-beta-driven Smad3 signaling and inhibiting IL-6 and IL-23 receptor expression[J]. J Immunol, 2008, 181(4): 2277-2284.
40. 　Keino H, Watanabe T, Sato Y, et al. Anti-inflammatory effect of retinoic acid on experimental autoimmune uveoretinitis[J]. Br J Ophthalmol, 2010, 94(6): 802-807.
  1. 1. 　Mosmann TR, Cherwinski H, Bond MW, et al. Two types of murine helper T cell clone. I. Definition according to profiles of lymphokine activities and secreted proteins[J]. J Immunol, 1986, 136(7): 2348-2357.
  2. 2. 　Cua DJ, Sherlock J, Chen Y, et al. Interleukin-23 rather than interleukin-12 is the critical cytokine for autoimmune inflammation of the brain[J]. Nature, 2003, 421(6924): 744-748.
  3. 3. 　Langrish CL, Chen Y, Blumenschein WM, et al. IL-23 drives a pathogenic T cell population that induces autoimmune inflammation[J]. J Exp Med, 2005, 201(2): 233-240.
  4. 4. 　Park H, Li Z, Yang XO, et al. A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17[J]. Nat Immunol, 2005, 6(11): 1133-1141.
  5. 5. 　Bettelli E, Carrier Y, Gao W, et al. Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells[J]. Nature, 2006, 441(7090): 235-238.
  6. 6. 　Korn T, Bettelli E, Gao W, et al. IL-21 initiates an alternative pathway to induce proinflammatory T(H)17 cells[J]. Nature, 2007, 448(7152): 484-487.
  7. 7. 　Yang L, Anderson DE, Baecher-Allan C, et al. IL-21 and TGF-beta are required for differentiation of human T(H)17 cells[J]. Nature, 2008, 454(7202): 350-352.
  8. 8. 　Yen D, Cheung J, Scheerens H, et al. IL-23 is essential for T cell-mediated colitis and promotes inflammation via IL-17 and IL-6[J]. J Clin Invest, 2006, 116(5): 1310-1316.
  9. 9. 　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[J]. Nat Immunol, 2005, 6(11): 1123-1132.
  10. 10. 　Aggarwal S, Ghilardi N, Xie MH, et al. Interleukin-23 promotes a distinct CD4 T cell activation state characterized by the production of interleukin-17[J]. J Biol Chem, 2003, 278(3): 1910-1914.
  11. 11. 　Chen Z, Laurence A, O’Shea JJ. Signal transduction pathways and transcriptional regulation in the control of Th17 differentiation[J]. Semin Immunol, 2007, 19(6): 400-408.
  12. 12. 　Ivanov II, McKenzie BS, Zhou L, et al. The orphan nuclear receptor RORgammat directs the differentiation program of proinflammatory IL-17+ T helper cells[J]. Cell, 2006, 126(6): 1121-1133.
  13. 13. 　Wei L, Laurence A, Elias KM, et al. IL-21 is produced by Th17 cells and drives IL-17 production in a STAT3-dependent manner[J]. J Biol Chem, 2007, 282(48): 34605-34610.
  14. 14. 　Joosten LA, Abdollahi-Roodsaz S, Heuvelmans-Jacobs M, et al. T cell dependence of chronic destructive murine arthritis induced by repeated local activation of Toll-like receptor-driven pathways: crucial role of both interleukin-1beta and interleukin-17[J]. Arthritis Rheum, 2008, 58(1): 98-108.
  15. 15. 　Mangan PR, Harrington LE, O’Quinn DB, et al. Transforming growth factor-beta induces development of the T(H)17 lineage[J]. Nature, 2006, 441(7090): 231-234.
  16. 16. 　Zhou L, Lopes JE, Chong MM, et al. TGF-beta-induced Foxp3 inhibits T(H)17 cell differentiation by antagonizing RORgammat function[J]. Nature, 2008, 453(7192): 236-240.
  17. 17. 　Niedbala W, Wei XQ, Cai B, et al. IL-35 is a novel cytokine with therapeutic effects against collagen-induced arthritis through the expansion of regulatory T cells and suppression of Th17 cells[J]. Eur J Immunol, 2007, 37(11): 3021-3029.
  18. 18. 　Batten M, Li J, Yi S, et al. Interleukin 27 limits autoimmune encephalomyelitis by suppressing the development of interleukin 17-producing T cells[J]. Nat Immunol, 2006, 7(9): 929-936.
  19. 19. 　McGeachy MJ, Bak-Jensen KS, Chen Y, et al. TGF-beta and IL-6 drive the production of IL-17 and IL-10 by T cells and restrain T(H)-17 cell-mediated pathology[J]. Nat Immunol, 2007, 8(12): 1390-1397.
  20. 20. 　Spolski R, Leonard WJ. Interleukin-21: basic biology and implications for cancer and autoimmunity[J]. Annu Rev Immunol, 2008, 26: 57-79.
  21. 21. 　Zheng Y, Danilenko DM, Valdez P, et al. Interleukin-22, a T(H)17 cytokine, mediates IL-23-induced dermal inflammation and acanthosis[J]. Nature, 2007, 445(7128): 648-651.
  22. 22. 　Caspi RR. Th1 and Th2 responses in pathogenesis and regulation of experimental autoimmune uveoretinitis[J]. Int Rev Immunol, 2002, 21(2-3): 197-208.
  23. 23. 　Amadi-Obi A, Yu CR, Liu X, et al. TH17 cells contribute to uveitis and scleritis and are expanded by IL-2 and inhibited by IL-27/STAT1[J]. Nat Med, 2007, 13(6): 711-718.
  24. 24. 　Luger D, Silver PB, Tang J, et al. Either a Th17 or a Th1 effector response can drive autoimmunity: conditions of disease induction affect dominant effector category[J]. J Exp Med, 2008, 205(4): 799-810.
  25. 25. 　Tarrant TK, Silver PB, Chan CC, et al. Endogenous IL-12 is required for induction and expression of experimental autoimmune uveitis[J]. J Immunol, 1998, 161(1): 122-127.
  26. 26. 　Yoshimura T, Sonoda KH, Ohguro N, et al. Involvement of Th17 cells and the effect of anti-IL-6 therapy in autoimmune uveitis[J]. Rheumatology (Oxford), 2009, 48(4): 347-354.
  27. 27. 　Brereton CF, Sutton CE, Lalor SJ, et al. Inhibition of ERK MAPK suppresses IL-23- and IL-1-driven IL-17 production and attenuates autoimmune disease[J]. J Immunol, 2009, 183(3): 1715-1723.
  28. 28. 　Liu X, Lee YS, Yu CR, et al. Loss of STAT3 in CD4+ T cells prevents development of experimental autoimmune diseases[J]. J Immunol, 2008, 180(9): 6070-6076.
  29. 29. 　Haak S, Croxford AL, Kreymborg K, et al. IL-17A and IL-17F do not contribute vitally to autoimmune neuro-inflammation in mice[J]. J Clin Invest, 2009, 119(1): 61-69.
  30. 30. 　Yoshimura T, Sonoda KH, Ohguro N, et al. Involvement of Th17 cells and the effect of anti-IL-6 therapy in autoimmune uveitis[J]. Rheumatology(Oxford), 2009, 48(4): 347-354.
  31. 31. 　Hohki S, Ohguro N, Haruta H, et al. Blockade of interleukin-6 signaling suppresses experimental autoimmune uveoretinitis by the inhibition of inflammatory Th17 responses[J]. Exp Eye Res, 2010, 91(2): 162-170.
  32. 32. 　Bain DL, Heneghan AF, Connaghan-Jones KD, et al. Nuclear receptor structure: implications for function[J]. Annu Rev Physiol, 2007, 69: 201-220.
  33. 33. 　Mucida D, Park Y, Kim G, et al. Reciprocal TH17 and regulatory T cell differentiation mediated by retinoic acid[J]. Science (NY), 2007, 317(5835): 256-260.
  34. 34. 　Sun CM, Hall JA, Blank RB, et al. Small intestine lamina propria dendritic cells promote de novo generation of Foxp3 T reg cells via retinoic acid[J]. J Exp Med, 2007, 204(8): 1775-1785.
  35. 35. 　Lathrop SK, Santacruz NA, Pham D, et al. Antigen-specific peripheral shaping of the natural regulatory T cell population[J]. J Exp Med, 2008, 205(13): 3105-3117.
  36. 36. 　Coombes JL, Siddiqui KR, Arancibia-Carcamo CV, et al. A functionally specialized population of mucosal CD103+ DCs induces Foxp3+ regulatory T cells via a TGF-beta and retinoic acid-dependent mechanism[J]. J Exp Med, 2007, 204(8): 1757-1764.
  37. 37. 　Elias KM, Laurence A, Davidson TS, et al. Retinoic acid inhibits Th17 polarization and enhances FoxP3 expression through a Stat-3/Stat-5 independent signaling pathway[J]. Blood, 2008, 111(3): 1013-1020.
  38. 38. 　Schambach F, Schupp M, Lazar MA, et al. Activation of retinoic acid receptor-alpha favours regulatory T cell induction at the expense of IL-17-secreting T helper cell differentiation[J]. Eur J Immuol, 2007, 37(9): 2396-2399.
  39. 39. 　Xiao S, Jin H, Korn T, et al. Retinoic acid increases Foxp3+ regulatory T cells and inhibits development of Th17 cells by enhancing TGF-beta-driven Smad3 signaling and inhibiting IL-6 and IL-23 receptor expression[J]. J Immunol, 2008, 181(4): 2277-2284.
  40. 40. 　Keino H, Watanabe T, Sato Y, et al. Anti-inflammatory effect of retinoic acid on experimental autoimmune uveoretinitis[J]. Br J Ophthalmol, 2010, 94(6): 802-807.