自然杀伤细胞通过树突状细胞调控衣原体肺部感染中Th17/Treg免疫应答平衡
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摘要
目的探索鼠衣原体(Cm)肺部感染中自然杀伤(NK)细胞调节Th17/Treg应答的作用机制。方法建立鼠Cm肺部感染模型,采用CD11c~+磁珠分选NK细胞去除鼠和同型对照抗体处理鼠的脾树突状细胞(DCs),转输至野生鼠体内,对应小鼠分为NK~-DCs组(n=13)和NK~+DCs组(n=13)。经Cm攻击感染后,比较两组小鼠疾病严重程度;流式细胞术分析脾和肺中Th17及Treg应答变化。结果与转输NK~+DCs小鼠相比,转输NK~-DCs的小鼠病情加重,表现为体质量下降、肺载菌量增加及病理损伤加重,同时脾和肺中Th17应答降低,Treg应答增强,Th17/Treg应答失衡,差异均有统计学意义。结论在Cm肺部感染中,NK细胞能够通过调控DCs有效启动Th17应答,抑制Treg应答,发挥抗感染免疫保护作用。
Objective To explore the mechanism of natural killer(NK) cells in regulating of Th17/Treg cell responses during chlamydia muridarum(Cm) lung infection. Methods A pulmonary infection model of Cm was established. The spleen dendritic cells(DCs) from Cm-infected mice with or without NK cells depletion were obtained by application of CD11 c~+ MicroBeads. The na?EF;ve mice were given intravenous injection of DCs from different groups of mice, and divided into NK~-DCs recipients group(n=13) and NK~+DCs recipients group(n=13). After adoptive transfer, the same infection method was used to recipient mice with Cm. The degree of disease was compared between the two groups. Flow cytometry was used to detect the changes of Th17 and Treg cells in the spleen and lung of mice. Results Compared with NK~+DCs recipients, NK~-DCs recipients exhibited aggravated disease, higher weight loss and severe lung injury. Immunological analysis showed the proportion of Th17 cells in spleen and lung was reduced while the proportion of Treg cell response was enhanced, which contributed to imbalance of Th17/Treg response in NK~-DCs recipients.Conclusion NK cells can effectively initiate Th17 cells response and inhibit Treg cell response by modulating DCs and thus play an important role in controlling chlamydial infection.
Objective To explore the mechanism of natural killer(NK) cells in regulating of Th17/Treg cell responses during chlamydia muridarum(Cm) lung infection. Methods A pulmonary infection model of Cm was established. The spleen dendritic cells(DCs) from Cm-infected mice with or without NK cells depletion were obtained by application of CD11 c~+ MicroBeads. The na?EF;ve mice were given intravenous injection of DCs from different groups of mice, and divided into NK~-DCs recipients group(n=13) and NK~+DCs recipients group(n=13). After adoptive transfer, the same infection method was used to recipient mice with Cm. The degree of disease was compared between the two groups. Flow cytometry was used to detect the changes of Th17 and Treg cells in the spleen and lung of mice. Results Compared with NK~+DCs recipients, NK~-DCs recipients exhibited aggravated disease, higher weight loss and severe lung injury. Immunological analysis showed the proportion of Th17 cells in spleen and lung was reduced while the proportion of Treg cell response was enhanced, which contributed to imbalance of Th17/Treg response in NK~-DCs recipients.Conclusion NK cells can effectively initiate Th17 cells response and inhibit Treg cell response by modulating DCs and thus play an important role in controlling chlamydial infection.
引文
[1] Elwell C, Mirrashidi K, Engel J. Chlamydia cell biology and pathogenesis[J]. Nat Rev Microbiol, 2016, 14(6): 385-400.
[2] Brunham RC, Rey-Ladino J. Immunology of Chlamydia infection: implications for a Chlamydia trachomatis vaccine[J]. Nat Rev Immunol, 2005, 5(2):149-161.
[3] 吴移谋. 衣原体[M]. 北京: 人民卫生出版社, 2012.
[4] Bai H, Cheng J, Gao X, et al. IL-17/Th17 promotes type 1 T cell immunity against pulmonary intracellular bacterial infection through modulating dendritic cell function[J]. J Immunol, 2009, 183(9): 5886-5895.
[5] 陈彦波, 吴移谋. Th17细胞在衣原体感染中的作用研究[J]. 微生物学免疫学进展, 2015, 43(2): 45-48CHEN Yanbo, WU Yimou. Role of Th17 cells in chlamydial infection[J]. Progress in Microbiology and Immunology, 2015, 43(2): 45-48.
[6] Zhang Y, Wang H, Ren J, et al. IL-17A synergizes with IFN-γ to upregulate iNOS and NO production and inhibit chlamydial growth[J]. PLoS One, 2012, 7(6): e39214. doi:10.1371/journal.pone.0039214.
[7] Labuda JC, McSorley SJ. Diversity in the T cell response to Chlamydia-sum are better than one[J]. Immunol Lett, 2018, 202: 59-64. doi:10.1016/j.imlet.2018.08.002.
[8] Stary G, Olive A, Radovic-Moreno AF, et al. VACCINES. A mucosal vaccine against Chlamydia trachomatis generates two waves of protective memory T cells[J]. Science, 2015, 348(6241): aaa8205. doi:10.1126/science.aaa8205.
[9] Noack M, Miossec P. Th17 and regulatory T cell balance in autoimmune and inflammatory diseases[J]. Autoimmun Rev, 2014, 13(6): 668-677.
[10] Yang H, Guo HZ, Li XY, et al. Viral RNA-unprimed RIG-I restrains Stat3 activation in the modulation of regulatory T cell/Th17 cell balance[J]. J Immunol, 2017, 199(1): 119-128.
[11] 胡亚南, 单永业, 罗亚文, 等. Th17/Treg比率在慢性乙型肝炎患者外周血的动态变化及意义[J]. 中国免疫学杂志, 2017, 33(7): 1072-1075. HU Ya?nan, SHAN Yongye, LUO Yawen, et al. Dynamic changes and significance of peripheral blood Th17/Treg in chronic hepatitis B patients[J]. Chinese Journal of Immunology, 2017, 33(7): 1072-1075.
[12] Li J, Dong X, Zhao L, et al. Natural killer cells regulate Th1/Treg and Th17/Treg balance in chlamydial lung infection[J]. J Cell Mol Med, 2016, 20(7): 1339-1351.
[13] 董晓婧, 李静, 赵蕾, 等. 鼠衣原体肺部感染中自然杀伤细胞对白细胞介素-22产生及疾病进程的影响[J]. 山东大学学报(医学版), 2016, 54(11): 19-23.DONG Xiaojing, LI Jing, ZHAO Lei, et al. Effect of natural killer cells on the production of interleukin-22 and disease process during Chlamydia muridarum lung infection[J]. Journal of Shandong University(Health Sciences), 2016, 54(11): 19-23.
[14] Zheng M, Sun R, Wei H, et al. NK cells help induce anti-hepatitis B virus CD8+ T cell immunity in mice[J]. J Immunol, 2016, 196(10): 4122-4131.
[15] Crouse J, Xu HC, Lang PA, et al. NK cells regulating T cell responses: mechanisms and outcome[J]. Trends Immunol, 2015, 36(1): 49-58.
[16] Jiao L, Gao X, Joyee AG, et al. NK cells promote type 1 T cell immunity through modulating the function of dendritic cells during intracellular bacterial infection[J]. J Immunol, 2011, 187(1): 401-411.
[17] Robbins SH, Bessou G, Cornillon A, et al. Natural killer cells promote early CD8 T cell responses against cytomegalovirus[J]. PLoS Pathog, 2007, 3(8): e123. doi:10.1371/journal.ppat.0030123.
[18] Moore-Connors JM, Fraser R, Halperin SA, et al. CD4+CD25+Foxp3+ regulatory T cells promote Th17 responses and genital tract inflammation upon intracellular Chlamydia muridarum infection[J]. J Immunol, 2013, 191(6): 3430-3439.
[19] Shekhar S, Peng Y, Gao XL, et al. NK cells modulate the lung dendritic cell-mediated Th1/Th17 immunity during intracellular bacterial infection[J]. Eur J Immunol, 2015, 45(10): 2810-2820.
[20] 赵国生, 徐晚雪, 王海萍, 等. 宿主的遗传背景对呼吸道感染沙眼衣原体后Treg产生的影响[J]. 中华微生物学和免疫学杂志, 2013, 33(3): 193-196. ZHAO Guosheng, XU Wanxue, WANG Haiping, et al. The different genetic background of inbred mouse strains affect Treg cells during Chlamydia muridarum lung infection[J]. Chinese Journal of Microbiology and Immunology, 2013, 33(3): 193-196.
[21] Mabey DC, Hu V, Bailey RL, et al. Towards a safe and effective chlamydial vaccine: lessons from the eye[J]. Vaccine, 2014, 32(14): 1572-1578.
[22] Cook KD, Waggoner SN, Whitmire JK. NK cells and their ability to modulate T cells during virus infections[J]. Crit Rev Immunol, 2014, 34(5): 359-388.
[23] Thomas R, Yang X. NK-DC crosstalk in immunity to microbial infection[J]. J Immunol Res, 2016, 2016: 6374379. doi:10.1155/2016/6374379.
[24] Andrews DM, Scalzo AA, Yokoyama WM, et al. Functional interactions between dendritic cells and NK cells during viral infection[J]. Nat Immunol, 2003, 4(2): 175-181.
[25] Ferlazzo G, Morandi B. Cross-talks between natural killer cells and distinct subsets of dendritic cells[J]. Front Immunol, 2014, 5: 159. doi:10.3389/fimmu.2014.00159.
[2] Brunham RC, Rey-Ladino J. Immunology of Chlamydia infection: implications for a Chlamydia trachomatis vaccine[J]. Nat Rev Immunol, 2005, 5(2):149-161.
[3] 吴移谋. 衣原体[M]. 北京: 人民卫生出版社, 2012.
[4] Bai H, Cheng J, Gao X, et al. IL-17/Th17 promotes type 1 T cell immunity against pulmonary intracellular bacterial infection through modulating dendritic cell function[J]. J Immunol, 2009, 183(9): 5886-5895.
[5] 陈彦波, 吴移谋. Th17细胞在衣原体感染中的作用研究[J]. 微生物学免疫学进展, 2015, 43(2): 45-48CHEN Yanbo, WU Yimou. Role of Th17 cells in chlamydial infection[J]. Progress in Microbiology and Immunology, 2015, 43(2): 45-48.
[6] Zhang Y, Wang H, Ren J, et al. IL-17A synergizes with IFN-γ to upregulate iNOS and NO production and inhibit chlamydial growth[J]. PLoS One, 2012, 7(6): e39214. doi:10.1371/journal.pone.0039214.
[7] Labuda JC, McSorley SJ. Diversity in the T cell response to Chlamydia-sum are better than one[J]. Immunol Lett, 2018, 202: 59-64. doi:10.1016/j.imlet.2018.08.002.
[8] Stary G, Olive A, Radovic-Moreno AF, et al. VACCINES. A mucosal vaccine against Chlamydia trachomatis generates two waves of protective memory T cells[J]. Science, 2015, 348(6241): aaa8205. doi:10.1126/science.aaa8205.
[9] Noack M, Miossec P. Th17 and regulatory T cell balance in autoimmune and inflammatory diseases[J]. Autoimmun Rev, 2014, 13(6): 668-677.
[10] Yang H, Guo HZ, Li XY, et al. Viral RNA-unprimed RIG-I restrains Stat3 activation in the modulation of regulatory T cell/Th17 cell balance[J]. J Immunol, 2017, 199(1): 119-128.
[11] 胡亚南, 单永业, 罗亚文, 等. Th17/Treg比率在慢性乙型肝炎患者外周血的动态变化及意义[J]. 中国免疫学杂志, 2017, 33(7): 1072-1075. HU Ya?nan, SHAN Yongye, LUO Yawen, et al. Dynamic changes and significance of peripheral blood Th17/Treg in chronic hepatitis B patients[J]. Chinese Journal of Immunology, 2017, 33(7): 1072-1075.
[12] Li J, Dong X, Zhao L, et al. Natural killer cells regulate Th1/Treg and Th17/Treg balance in chlamydial lung infection[J]. J Cell Mol Med, 2016, 20(7): 1339-1351.
[13] 董晓婧, 李静, 赵蕾, 等. 鼠衣原体肺部感染中自然杀伤细胞对白细胞介素-22产生及疾病进程的影响[J]. 山东大学学报(医学版), 2016, 54(11): 19-23.DONG Xiaojing, LI Jing, ZHAO Lei, et al. Effect of natural killer cells on the production of interleukin-22 and disease process during Chlamydia muridarum lung infection[J]. Journal of Shandong University(Health Sciences), 2016, 54(11): 19-23.
[14] Zheng M, Sun R, Wei H, et al. NK cells help induce anti-hepatitis B virus CD8+ T cell immunity in mice[J]. J Immunol, 2016, 196(10): 4122-4131.
[15] Crouse J, Xu HC, Lang PA, et al. NK cells regulating T cell responses: mechanisms and outcome[J]. Trends Immunol, 2015, 36(1): 49-58.
[16] Jiao L, Gao X, Joyee AG, et al. NK cells promote type 1 T cell immunity through modulating the function of dendritic cells during intracellular bacterial infection[J]. J Immunol, 2011, 187(1): 401-411.
[17] Robbins SH, Bessou G, Cornillon A, et al. Natural killer cells promote early CD8 T cell responses against cytomegalovirus[J]. PLoS Pathog, 2007, 3(8): e123. doi:10.1371/journal.ppat.0030123.
[18] Moore-Connors JM, Fraser R, Halperin SA, et al. CD4+CD25+Foxp3+ regulatory T cells promote Th17 responses and genital tract inflammation upon intracellular Chlamydia muridarum infection[J]. J Immunol, 2013, 191(6): 3430-3439.
[19] Shekhar S, Peng Y, Gao XL, et al. NK cells modulate the lung dendritic cell-mediated Th1/Th17 immunity during intracellular bacterial infection[J]. Eur J Immunol, 2015, 45(10): 2810-2820.
[20] 赵国生, 徐晚雪, 王海萍, 等. 宿主的遗传背景对呼吸道感染沙眼衣原体后Treg产生的影响[J]. 中华微生物学和免疫学杂志, 2013, 33(3): 193-196. ZHAO Guosheng, XU Wanxue, WANG Haiping, et al. The different genetic background of inbred mouse strains affect Treg cells during Chlamydia muridarum lung infection[J]. Chinese Journal of Microbiology and Immunology, 2013, 33(3): 193-196.
[21] Mabey DC, Hu V, Bailey RL, et al. Towards a safe and effective chlamydial vaccine: lessons from the eye[J]. Vaccine, 2014, 32(14): 1572-1578.
[22] Cook KD, Waggoner SN, Whitmire JK. NK cells and their ability to modulate T cells during virus infections[J]. Crit Rev Immunol, 2014, 34(5): 359-388.
[23] Thomas R, Yang X. NK-DC crosstalk in immunity to microbial infection[J]. J Immunol Res, 2016, 2016: 6374379. doi:10.1155/2016/6374379.
[24] Andrews DM, Scalzo AA, Yokoyama WM, et al. Functional interactions between dendritic cells and NK cells during viral infection[J]. Nat Immunol, 2003, 4(2): 175-181.
[25] Ferlazzo G, Morandi B. Cross-talks between natural killer cells and distinct subsets of dendritic cells[J]. Front Immunol, 2014, 5: 159. doi:10.3389/fimmu.2014.00159.