滤泡辅助性T细胞及其与系统性红斑狼疮关系的研究进展_West China Medical Journal

Authors：

 赵娟 , 李立新 ,  武永康

四川大学华西医院实验医学科, 成都 610041;

Corresponding author：

赵娟, Email: 1204843963@qq.com; 武永康, Email: vipwyk@163.com

Keywords：

滤泡辅助性T细胞; 系统性红斑狼疮; 发病机制; 治疗

DOI：

10.7507/1002-0179.201600309

Video：

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Abstract Full text Figures/Tables Video References Cited by

滤泡辅助性 T 细胞（Tfh）是近年来发现的辅助 B 细胞发生体液免疫的一类新的 CD4⁺T 细胞亚群，其具有特异的细胞识别表位（CD4⁺CXCR5⁺）和主要的信号传导分子（BCL-6、诱导性协同共刺激分子、程序性细胞死亡蛋白-1），并能分泌一系列细胞因子 [白细胞介素（IL）-21、IL-6、IL-27 等 ]。Tfh 在 B 细胞的发育、分化，抗体的产生和类型转换以及生发中心的形成中发挥重要作用。Tfh 细胞数量及其效应分子的异常与多种自身免疫性疾病密切相关，系统性红斑狼疮（SLE）是一种发病率较高的典型的自身免疫性疾病。该文主要综述了 Tfh 细胞的特征、功能、分化发育及其与 SLE 的关系，深入研究 Tfh 细胞可能为治疗 SLE 发现新的治疗靶点和方向。

Citation： 赵娟, 李立新, 武永康. 滤泡辅助性T细胞及其与系统性红斑狼疮关系的研究进展. West China Medical Journal, 2016, 31(6): 1142-1146. doi: 10.7507/1002-0179.201600309 Copy

1.	Breitfeld D, Ohl L, Kremmer E, et al. Follicular B helper T cells Express CXC chemokine receptor 5, localize to B cell follicles, and support immunoglobulin production[J]. J Exp Med, 2000, 192(11) : 1545-1552.
2.	Allen CD, Okada T, Cyster JG. Germinal-center organization and cellular dynamics[J]. Immunity, 2007, 27(2) :190-202.
3.	Linterman MA, Liston A, Vinuesa CG. T-follicular helper cell differentiation and the co-option of this pathway by non-helper cells[J]. Immunol Rev, 2012, 247(1) :143-159.
4.	Murphy KM, Reiner SL. The lineage decisions of helper T cells[J]. Nat Rev Immunol, 2002, 2(12) :933-944.
5.	King C, Tangye SG, Mackay CR. T follicular helper (TFH) cells in normal and dysregulated immune responses[J]. Annu Rev Immunol, 2008, 26:741-766.
6.	Kim CH, Rott LS, Clark-Lewis I, et al. Subspecialization of CXCR5+ T cells:B helper activity is focused in a germinal center-localized subset of CXCR5+ T cells[J]. J Exp Med, 2001, 193(12) :1373-1381.
7.	Akiba H, Takeda K, Kojima Y, et al. The role of ICOS in the CXCR5+ follicular B helper T cell maintenance in vivo[J]. J Immunol, 2005, 175(4) :2340-2348.
8.	Dong C, Juedes AE, Temann UA, et al. ICOS co-stimulatory receptor is essential for T-cell activation and function[J]. Nature, 2001, 409(6816) :97-101.
9.	Bauquet AT, Jin H, Paterson AM, et al. Costimulatory molecule ICOS plays a critical role in the development of TH-17 and follicular T-helper cells by regulating c-Maf expression and IL-21 production[J]. Nat Immunol, 2009, 10(2) :167.
10.	Haymaker C, Wu R, Bernatchez C, et al. PD-1 and BTLA and CD8⁺ T-cell "exhaustion" in cancer:"Exercising" an alternative viewpoint[J]. Oncoimmunology, 2012, 1(5) :735-738.
11.	Riella LV, Paterson AM, Sharpe AH, et al. Role of the PD-1 pathway in the immune response[J]. Am J Transplant, 2012, 12(10) :2575-2587.
12.	Renshaw BR, Fanslow WC, Armitage RJ, et al. Humoral immune responses in CD40 ligand-deficient mice[J]. J Exp Med, 1994, 180(5) :1889-1900.
13.	Kawabe T, Naka T, Yoshida K, et al. The immune responses in CD40-deficient mice:impaired immunoglobulin class switching and germinal center formation[J]. Immunity, 1994, 1(3) :167-178.
14.	Bryant VL, Ma CS, Avery DT, et al. Cytokine-mediated regulation of human B cell differentiation into Ig-secreting cells:predominant role of IL-21 produced by CXCR5⁺ T follicular helper cells[J]. J Immunol, 2007, 179(12) :8180-8190.
15.	Liu Y, Zhu T, Cai G, et al. Elevated circulating CD4⁺ ICOS⁺ Foxp3⁺ T cells contribute to overproduction of IL-10 and are correlated with disease severity in patients with systemic lupus erythematosus[J]. Lupus, 2011, 20(6) :620-627.
16.	Ettinger R, Sims GP, Fairhurst AM, et al. IL-21 induces differentiation of human naive and memory B cells into antibodysecreting plasma cells[J]. J Immunol, 2005, 175(12) :7867-7879.
17.	Kuchen S, Robbins R, Sims GP, et al. Essential role of IL-21 in B cell activation, expansion, and plasma cell generation during CD4⁺ T cell-B cell collaboration[J]. J Immunol, 2007, 179(9) :5886-5896.
18.	Suto A, Kashiwakuma D, Kagami S, et al. Development and characterization of IL-21-producing CD4⁺ T cells[J]. J Exp Med, 2008, 205(6) :1369-1379.
19.	Eto D, Lao C, Ditoro D, et al. IL-21 and IL-6 are critical for different aspects of B cell immunity and redundantly induce optimal follicular helper CD4 T cell (Tfh) differentiation[J]. PLoS One, 2011, 6(3) : e17739.
20.	Kusam S, Toney LM, Sato H, et al. Inhibition of Th2 differentiation and GATA-3 expression by BCL-6[J]. J Immunol, 2003, 170(5) : 2435-2441.
21.	Dent AL, Shaffer AL, Yu X, et al. Control of inflammation, cytokine expression, and germinal center formation by BCL-6[J]. Science, 1997, 276(5312) :589-592.
22.	Ozaki K, Spolski R, Ettinger R, et al. Regulation of B cell differentiation and plasma cell Generation by IL-21, a novel inducer of Blimp-1 and Bcl-6[J]. J Immunol, 2004, 173(9) :5361-5371.
23.	Luther SA, Bidgol A, Hargreaves DC, et al. Differing activities of homeostatic chemokines CCL19, CCL21, and CXCL12 in lymphocyte and dendritic cell recruitment and lymphoid neogenesis[J]. J Immunol, 2002, 169(1) :424-433.
24.	Haynes NM, Allen CD, Lesley R, et al. Role of CXCR5 and CCR7 in follicular Th cell positioning and appearance of a programmed cell death gene-1high germinal center-associated subpopulation[J]. J Immunol, 2007, 179(8) :5099-5108.
25.	Allen CD, Ansel KM, Low C, et al. Germinal center dark and light zone organization is mediated by CXCR4 and CXCR5[J]. Nat Immunol, 2004, 5(9) :943-952.
26.	Xu H, Li X, Liu D, et al. Follicular T-helper cell recruitment governed by bystander B cells and ICOS-driven motility[J]. Nature, 2013, 496(7446) :523-527.
27.	Nurieva RI, Chung Y, Martinez GJ, et al. Bcl6 mediates the development of T follicular helper cells[J]. Science, 2009, 325(5943) : 1001-1005.
28.	Johnston RJ, Choi YS, Diamond JA, et al. STAT5 is a potent negative regulator of TFH cell differentiation[J]. J Exp Med, 2012, 209(2) : 243-250.
29.	Choi YS, Yang JA, Crotty S. Dynamic regulation of Bcl6 in follicular helper CD4 T (Tfh) cells[J]. Curr Opin Immunol, 2013, 25(3) :366-372.
30.	Kitano M, Moriyama S, Ando Y, et al. Bcl6 protein expression shapes pre-germinal center B cell dynamics and follicular helper T cell heterogeneity[J]. Immunity, 2011, 34(6) :961-972.
31.	Yu D, Rao S, Tsai LM, et al. The transcriptional repressor Bcl-6 directs T follicular helper cell lineage commitment[J]. Immunity, 2009, 31(3) :457-468.
32.	Cobb BS, Nesterova TB, Thompson E, et al. T cell lineage choice and differentiation in the absence of the RNase Ⅲ enzyme Dicer[J]. J Exp Med, 2005, 201(9) :1367-1373.
33.	Kang SG, Liu WH, Lu P, et al. MicroRNAs of the miR-17~92 family are critical regulators of T(FH) differentiation[J]. Nat Immunol, 2013, 14(8) :849-857.
34.	Baumjohann D, Kageyama R, Clingan JM, et al. The microRNA cluster miR-17~92 promotes TFH cell differentiation and represses subset-inappropriate gene expression[J]. Nat Immunol, 2013, 14(8) : 840-848.
35.	Takahashi H, Kanno T, Nakayamada SA, et al. TGF-beta and retinoic acid induce the microRNA miR-10a, which targets Bcl-6 and constrains the plasticity of helper T cells[J]. Nat Immunol, 2012, 13(6) :587.
36.	Luzina IG, Atamas SP, Storrer CE, et al. Spontaneous formation of germinal centers in autoimmune mice[J]. J Leukoc Biol, 2001, 70(4) : 578-584.
37.	Simpson N, Gatenby PA, Wilson A, et al. Expansion of circulating T cells resembling follicular helper T cells is a fixed phenotype that identifies a subset of severe systemic lupus erythematosus[J]. Arthritis Rheum, 2010, 62(1) :234-244.
38.	Vinuesa CG, Cook MC, Angelucci C, et al. A RING-type ubiquitin ligase family member required to repress follicular helper T cells and autoimmunity[J]. Nature, 2005, 435(741) :452-458.
39.	Zhang X, Lindwall E, Gauthier C, et al. Circulating CXCR5+ CD4⁺ helper T cells in systemic lupus erythematosus patients share phenotypic properties with germinal center follicular helper T cells and promote antibody production[J]. Lupus, 2015, 24(9) :909-917.
40.	Dolff S, Abdulahad WH, Westra J, et al. Increase in IL-21 producing T-cells in patients with systemic lupus erythematosus[J]. Arthritis Res Ther, 2011, 13(5) :R157.
41.	赵洁, 曾莉, 陈元, 等. 系统性红斑狼疮患儿外周血滤泡辅助性T细胞相关细胞因子及受体表达水平研究[J]. 重庆医学, 2014, 43(21) :2689-2690, 2694.
42.	Wang JL, Hao PP, Chen YG. Angiotensin Ⅱ type 1 receptor gene A1166C polymorphism and essential hypertension in Chinese: a meta-analysis[J]. J Renin Angiotensin Aldosterone Syst, 2010, 11(2) :127-135.
43.	Timaru-Kast R, Wyschkon S, Luh C, et al. Delayed inhibition of angiotensin Ⅱ receptor type 1 reduces secondary brain damage and improves functional recovery after experimental brain trauma[J]. Crit Care Med, 2012, 40(3) :935-944.
44.	Wong CK, Wong PT, Tam LS, et al. Elevated production of B cell chemokine CXCL13 is correlated with systemic lupus erythematosus disease activity[J]. J Clin Immunol, 2010, 30(1) :45-52.
45.	董大群, 王忠永, 李海英, 等. 系统性红斑狼疮患者外周血滤泡辅助性T细胞水平的检测[J]. 中国皮肤性病学杂志, 2014, 28(10) : 1007-1011.
46.	Le Coz C, Joublin A, Pasquali JL, et al. Circulating TFH subset distribution is strongly affected in lupus patients with an active disease[J]. PLoS One, 2013, 8(9) :e75319.
47.	Kim HJ, Verbinnen B, Tang XL, et al. Inhibition of follicular T-helper cells by CD8(+) regulatory T cells is essential for self tolerance[J]. Nature, 2010, 467(7313) :328-U107.
48.	Yang X, Yang J, Chu Y, et al. T follicular helper cells and regulatory B cells dynamics in systemic lupus erythematosus[J]. PLoS One, 2014, 9(2) :e88441.
49.	Linterman MA, Rigby RJ, Wong RK, et al. Follicular helper T cells are required for systemic autoimmunity[J]. J Exp Med, 2009, 206(3) : 561-576.
50.	Sinn DI, Lee ST, Chu K, et al. Combined neuroprotective effects of celecoxib and memantine in experimental intracerebral hemorrhage[J]. Neurosci Lett, 2007, 411(3) :238-242.
51.	Feng X, Wang D, Chen J, et al. Inhibition of aberrant circulating Tfh cell proportions by corticosteroids in patients with systemic lupus erythematosus[J]. PLoS One, 2012, 7(12) :e51982.
52.	Terrier B, Costedoat-Chalumeau N, Garrido M, et al. Interleukin 21 correlates with T cell and B cell subset alterations in systemic lupus erythematosus[J]. J Rheumatol, 2012, 39(9) :1819-1828.

1. Breitfeld D, Ohl L, Kremmer E, et al. Follicular B helper T cells Express CXC chemokine receptor 5, localize to B cell follicles, and support immunoglobulin production[J]. J Exp Med, 2000, 192(11) : 1545-1552.
2. Allen CD, Okada T, Cyster JG. Germinal-center organization and cellular dynamics[J]. Immunity, 2007, 27(2) :190-202.
3. Linterman MA, Liston A, Vinuesa CG. T-follicular helper cell differentiation and the co-option of this pathway by non-helper cells[J]. Immunol Rev, 2012, 247(1) :143-159.
4. Murphy KM, Reiner SL. The lineage decisions of helper T cells[J]. Nat Rev Immunol, 2002, 2(12) :933-944.
5. King C, Tangye SG, Mackay CR. T follicular helper (TFH) cells in normal and dysregulated immune responses[J]. Annu Rev Immunol, 2008, 26:741-766.
6. Kim CH, Rott LS, Clark-Lewis I, et al. Subspecialization of CXCR5+ T cells:B helper activity is focused in a germinal center-localized subset of CXCR5+ T cells[J]. J Exp Med, 2001, 193(12) :1373-1381.
7. Akiba H, Takeda K, Kojima Y, et al. The role of ICOS in the CXCR5+ follicular B helper T cell maintenance in vivo[J]. J Immunol, 2005, 175(4) :2340-2348.
8. Dong C, Juedes AE, Temann UA, et al. ICOS co-stimulatory receptor is essential for T-cell activation and function[J]. Nature, 2001, 409(6816) :97-101.
9. Bauquet AT, Jin H, Paterson AM, et al. Costimulatory molecule ICOS plays a critical role in the development of TH-17 and follicular T-helper cells by regulating c-Maf expression and IL-21 production[J]. Nat Immunol, 2009, 10(2) :167.
10. Haymaker C, Wu R, Bernatchez C, et al. PD-1 and BTLA and CD8⁺ T-cell "exhaustion" in cancer:"Exercising" an alternative viewpoint[J]. Oncoimmunology, 2012, 1(5) :735-738.
11. Riella LV, Paterson AM, Sharpe AH, et al. Role of the PD-1 pathway in the immune response[J]. Am J Transplant, 2012, 12(10) :2575-2587.
12. Renshaw BR, Fanslow WC, Armitage RJ, et al. Humoral immune responses in CD40 ligand-deficient mice[J]. J Exp Med, 1994, 180(5) :1889-1900.
13. Kawabe T, Naka T, Yoshida K, et al. The immune responses in CD40-deficient mice:impaired immunoglobulin class switching and germinal center formation[J]. Immunity, 1994, 1(3) :167-178.
14. Bryant VL, Ma CS, Avery DT, et al. Cytokine-mediated regulation of human B cell differentiation into Ig-secreting cells:predominant role of IL-21 produced by CXCR5⁺ T follicular helper cells[J]. J Immunol, 2007, 179(12) :8180-8190.
15. Liu Y, Zhu T, Cai G, et al. Elevated circulating CD4⁺ ICOS⁺ Foxp3⁺ T cells contribute to overproduction of IL-10 and are correlated with disease severity in patients with systemic lupus erythematosus[J]. Lupus, 2011, 20(6) :620-627.
16. Ettinger R, Sims GP, Fairhurst AM, et al. IL-21 induces differentiation of human naive and memory B cells into antibodysecreting plasma cells[J]. J Immunol, 2005, 175(12) :7867-7879.
17. Kuchen S, Robbins R, Sims GP, et al. Essential role of IL-21 in B cell activation, expansion, and plasma cell generation during CD4⁺ T cell-B cell collaboration[J]. J Immunol, 2007, 179(9) :5886-5896.
18. Suto A, Kashiwakuma D, Kagami S, et al. Development and characterization of IL-21-producing CD4⁺ T cells[J]. J Exp Med, 2008, 205(6) :1369-1379.
19. Eto D, Lao C, Ditoro D, et al. IL-21 and IL-6 are critical for different aspects of B cell immunity and redundantly induce optimal follicular helper CD4 T cell (Tfh) differentiation[J]. PLoS One, 2011, 6(3) : e17739.
20. Kusam S, Toney LM, Sato H, et al. Inhibition of Th2 differentiation and GATA-3 expression by BCL-6[J]. J Immunol, 2003, 170(5) : 2435-2441.
21. Dent AL, Shaffer AL, Yu X, et al. Control of inflammation, cytokine expression, and germinal center formation by BCL-6[J]. Science, 1997, 276(5312) :589-592.
22. Ozaki K, Spolski R, Ettinger R, et al. Regulation of B cell differentiation and plasma cell Generation by IL-21, a novel inducer of Blimp-1 and Bcl-6[J]. J Immunol, 2004, 173(9) :5361-5371.
23. Luther SA, Bidgol A, Hargreaves DC, et al. Differing activities of homeostatic chemokines CCL19, CCL21, and CXCL12 in lymphocyte and dendritic cell recruitment and lymphoid neogenesis[J]. J Immunol, 2002, 169(1) :424-433.
24. Haynes NM, Allen CD, Lesley R, et al. Role of CXCR5 and CCR7 in follicular Th cell positioning and appearance of a programmed cell death gene-1high germinal center-associated subpopulation[J]. J Immunol, 2007, 179(8) :5099-5108.
25. Allen CD, Ansel KM, Low C, et al. Germinal center dark and light zone organization is mediated by CXCR4 and CXCR5[J]. Nat Immunol, 2004, 5(9) :943-952.
26. Xu H, Li X, Liu D, et al. Follicular T-helper cell recruitment governed by bystander B cells and ICOS-driven motility[J]. Nature, 2013, 496(7446) :523-527.
27. Nurieva RI, Chung Y, Martinez GJ, et al. Bcl6 mediates the development of T follicular helper cells[J]. Science, 2009, 325(5943) : 1001-1005.
28. Johnston RJ, Choi YS, Diamond JA, et al. STAT5 is a potent negative regulator of TFH cell differentiation[J]. J Exp Med, 2012, 209(2) : 243-250.
29. Choi YS, Yang JA, Crotty S. Dynamic regulation of Bcl6 in follicular helper CD4 T (Tfh) cells[J]. Curr Opin Immunol, 2013, 25(3) :366-372.
30. Kitano M, Moriyama S, Ando Y, et al. Bcl6 protein expression shapes pre-germinal center B cell dynamics and follicular helper T cell heterogeneity[J]. Immunity, 2011, 34(6) :961-972.
31. Yu D, Rao S, Tsai LM, et al. The transcriptional repressor Bcl-6 directs T follicular helper cell lineage commitment[J]. Immunity, 2009, 31(3) :457-468.
32. Cobb BS, Nesterova TB, Thompson E, et al. T cell lineage choice and differentiation in the absence of the RNase Ⅲ enzyme Dicer[J]. J Exp Med, 2005, 201(9) :1367-1373.
33. Kang SG, Liu WH, Lu P, et al. MicroRNAs of the miR-17~92 family are critical regulators of T(FH) differentiation[J]. Nat Immunol, 2013, 14(8) :849-857.
34. Baumjohann D, Kageyama R, Clingan JM, et al. The microRNA cluster miR-17~92 promotes TFH cell differentiation and represses subset-inappropriate gene expression[J]. Nat Immunol, 2013, 14(8) : 840-848.
35. Takahashi H, Kanno T, Nakayamada SA, et al. TGF-beta and retinoic acid induce the microRNA miR-10a, which targets Bcl-6 and constrains the plasticity of helper T cells[J]. Nat Immunol, 2012, 13(6) :587.
36. Luzina IG, Atamas SP, Storrer CE, et al. Spontaneous formation of germinal centers in autoimmune mice[J]. J Leukoc Biol, 2001, 70(4) : 578-584.
37. Simpson N, Gatenby PA, Wilson A, et al. Expansion of circulating T cells resembling follicular helper T cells is a fixed phenotype that identifies a subset of severe systemic lupus erythematosus[J]. Arthritis Rheum, 2010, 62(1) :234-244.
38. Vinuesa CG, Cook MC, Angelucci C, et al. A RING-type ubiquitin ligase family member required to repress follicular helper T cells and autoimmunity[J]. Nature, 2005, 435(741) :452-458.
39. Zhang X, Lindwall E, Gauthier C, et al. Circulating CXCR5+ CD4⁺ helper T cells in systemic lupus erythematosus patients share phenotypic properties with germinal center follicular helper T cells and promote antibody production[J]. Lupus, 2015, 24(9) :909-917.
40. Dolff S, Abdulahad WH, Westra J, et al. Increase in IL-21 producing T-cells in patients with systemic lupus erythematosus[J]. Arthritis Res Ther, 2011, 13(5) :R157.
41. 赵洁, 曾莉, 陈元, 等. 系统性红斑狼疮患儿外周血滤泡辅助性T细胞相关细胞因子及受体表达水平研究[J]. 重庆医学, 2014, 43(21) :2689-2690, 2694.
42. Wang JL, Hao PP, Chen YG. Angiotensin Ⅱ type 1 receptor gene A1166C polymorphism and essential hypertension in Chinese: a meta-analysis[J]. J Renin Angiotensin Aldosterone Syst, 2010, 11(2) :127-135.
43. Timaru-Kast R, Wyschkon S, Luh C, et al. Delayed inhibition of angiotensin Ⅱ receptor type 1 reduces secondary brain damage and improves functional recovery after experimental brain trauma[J]. Crit Care Med, 2012, 40(3) :935-944.
44. Wong CK, Wong PT, Tam LS, et al. Elevated production of B cell chemokine CXCL13 is correlated with systemic lupus erythematosus disease activity[J]. J Clin Immunol, 2010, 30(1) :45-52.
45. 董大群, 王忠永, 李海英, 等. 系统性红斑狼疮患者外周血滤泡辅助性T细胞水平的检测[J]. 中国皮肤性病学杂志, 2014, 28(10) : 1007-1011.
46. Le Coz C, Joublin A, Pasquali JL, et al. Circulating TFH subset distribution is strongly affected in lupus patients with an active disease[J]. PLoS One, 2013, 8(9) :e75319.
47. Kim HJ, Verbinnen B, Tang XL, et al. Inhibition of follicular T-helper cells by CD8(+) regulatory T cells is essential for self tolerance[J]. Nature, 2010, 467(7313) :328-U107.
48. Yang X, Yang J, Chu Y, et al. T follicular helper cells and regulatory B cells dynamics in systemic lupus erythematosus[J]. PLoS One, 2014, 9(2) :e88441.
49. Linterman MA, Rigby RJ, Wong RK, et al. Follicular helper T cells are required for systemic autoimmunity[J]. J Exp Med, 2009, 206(3) : 561-576.
50. Sinn DI, Lee ST, Chu K, et al. Combined neuroprotective effects of celecoxib and memantine in experimental intracerebral hemorrhage[J]. Neurosci Lett, 2007, 411(3) :238-242.
51. Feng X, Wang D, Chen J, et al. Inhibition of aberrant circulating Tfh cell proportions by corticosteroids in patients with systemic lupus erythematosus[J]. PLoS One, 2012, 7(12) :e51982.
52. Terrier B, Costedoat-Chalumeau N, Garrido M, et al. Interleukin 21 correlates with T cell and B cell subset alterations in systemic lupus erythematosus[J]. J Rheumatol, 2012, 39(9) :1819-1828.

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滤泡辅助性T细胞及其与系统性红斑狼疮关系的研究进展

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