滤泡辅助性T细胞(Tfh)在乳腺癌中的作用
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摘要
滤泡辅助性T细胞(Tfh)是一种特殊类型的辅助性T细胞,位于生发中心的Tfh细胞表达CXCR5、Bcl-6、IL-21、CXCL13等分子,通过协助B细胞的分化在体液免疫应答过程中发挥关键作用。借助于流式细胞术、免疫组化等方法,发现Tfh细胞也存在于乳腺癌肿瘤组织中,其表型为PD-1~(hi)CXCR5-ICOS~(int)Bcl-6~(int)IL-21~+CXCL13~+,提示其参与了抗肿瘤免疫。Tfh细胞相关基因,特别是CXCL13基因的表达对乳腺癌预后判断有一定的价值。位于乳腺癌淋巴结中的Tfh细胞呈CXCR5~+Bcl-6~+Foxp3~-,可能接受其他CD4~+T细胞的调控或与其协同作用,影响体液免疫应答。目前对乳腺癌Tfh细胞的功能特征和预后价值尚缺乏系统和深入的研究,以乳腺癌Tfh细胞为靶点的进一步研究将有助于加深对乳腺癌肿瘤微环境的认识,同时也有可能为今后乳腺癌的免疫干预提供潜在的靶点。
T follicular helper( Tfh) cells,which form germinal center,are a distinct subpopulation of helper T cells. Tfh cells express high level of CXCR5,Bcl-6,IL-21,CXCL13 and other characteristic markers. In addition,they provide essential support for B cells to regulate the humoral response. Several findings by flow cytometry and IHC indicate that Tfh cells also exist in breast cancer tissues,with the phenotype of PD-1 ~(hi)CXCR5-ICOS~(int)Bcl-6 ~(int)IL-21~+CXCL13~+and are involved in the anti-tumor immunity. Besides,Tfhassociated genes like CXCL13 represent predictive value in breast cancer. However,Tfh cells in lymph nodes of breast cancer have the different phenotype of CXCR5~+Bcl-6~+Foxp3~-. They may enhance the humoral response by the regulation or cooperation of other CD4~+T cells. The functional role and prognostic value of Tfh cells in breast cancer still remain elusive. Researches on Tfh cells not only help us to understand the complexity of tumor microenvironment but also constitute potential targets for the immune inference in breast cancer.
T follicular helper( Tfh) cells,which form germinal center,are a distinct subpopulation of helper T cells. Tfh cells express high level of CXCR5,Bcl-6,IL-21,CXCL13 and other characteristic markers. In addition,they provide essential support for B cells to regulate the humoral response. Several findings by flow cytometry and IHC indicate that Tfh cells also exist in breast cancer tissues,with the phenotype of PD-1 ~(hi)CXCR5-ICOS~(int)Bcl-6 ~(int)IL-21~+CXCL13~+and are involved in the anti-tumor immunity. Besides,Tfhassociated genes like CXCL13 represent predictive value in breast cancer. However,Tfh cells in lymph nodes of breast cancer have the different phenotype of CXCR5~+Bcl-6~+Foxp3~-. They may enhance the humoral response by the regulation or cooperation of other CD4~+T cells. The functional role and prognostic value of Tfh cells in breast cancer still remain elusive. Researches on Tfh cells not only help us to understand the complexity of tumor microenvironment but also constitute potential targets for the immune inference in breast cancer.
引文
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[32] Crotty S,Johnston RJ,Schoenberger SP. Effectors and memories:Bcl-6 and Blimp-1 in T and B lymphocyte differentiation[J]. Nat Immunol,2010,11(2):114-120.
[33] Winstead CJ,Weaver CT. Dwelling on T cell fate decisions[J].Cell,2013,153(4):739-741.
[34] Sopel N,Graser A,Mousset S,et al. The transcription factor BATF modulates cytokine-mediated responses in T cells[J]. Cytokine Growth Factor Rev,2016,30:39-45.
[35] Mcdonald PW,Read KA,Baker CE,et al. IL-7 signalling represses Bcl-6 and the TFH gene program[J]. Nat Commun,2016,7:10285.
[36] Mathew R,Mao AP,Chiang AH,et al. A negative feedback loop mediated by the Bcl6-cullin 3 complex limits Tfh cell differentiation[J]. J Exp Med,2014,211(6):1137-1151.
[37]冯俊燕,牛俊奇,姜艳芳.滤泡性辅助性T细胞(Tfh)的研究进展[J].中国免疫学杂志,2010,26(8):754-757.Feng JY,Niu JQ,Jiang YF. Recent progress in study on T follicular helper cells(Tfh)[J]. Chin J Immunol,2010,26(8):754-757.
[38] Zotos D,Coquet JM,Zhang Y,et al. IL-21 regulates germinal center B cell differentiation and proliferation through a B cellintrinsic mechanism[J]. J Exp Med,2010,207(2):365-378.
[39] Kwon H,Thierry-Mieg D,Thierry-Mieg J,et al. Analysis of interleukin-21-induced Prdm1 gene regulation reveals functional cooperation of STAT3 and IRF4 transcription factors[J].Immunity,2009,31(6):941-952.
[40] Weinstein JS,Herman EI,Lainez B,et al. TFH cells progressively differentiate to regulate the germinal center response[J]. Nat Immunol,2016,17(10):1197-1205.
[41] Mcguire H M,Vogelzang A,Warren J,et al. IL-21 and IL-4collaborate to shape T-dependent antibody responses[J]. J Immunol,2015,195(11):5123-5135.
[2] Schultz BT,Teigler JE,Pissani F,et al. Circulating HIV-specific interleukin-21(+)CD4(+)T cells represent peripheral tfh cells with antigen-dependent helper functions[J]. Immunity,2016,44(1):167-178.
[3] Chen MM,Xiao X,Lao XM,et al. Polarization of tissue-resident TFH-like cells in human hepatoma bridges innate monocyte inflammation and M2b macrophage polarization[J]. Cancer Discov,2016,6(10):1182-1195.
[4] Rao DA,Gurish MF,Marshall JL,et al. Pathologically expanded peripheral T helper cell subset drives B cells in rheumatoid arthritis[J]. Nature,2017,542(7639):110-114.
[5]王俊文,官杰. Tfh细胞与临床疾病的研究进展[J].齐齐哈尔医学院学报,2014,35(15):2292-2293.Wang JW,Guan J. Recent progress in Tfh cells with clinical diseases[J]. J Qiqihar Univ Med,2014,35(15):2292-2293.
[6]邹弋华,付占威,陈广洁. Tfh与Tfr的研究进展及其在类风湿性关节炎发展中的作用[J].现代免疫学,2017,37(2):170-173,169.Zou YH,Fu ZW,Chen GJ. Recent progress in Tfh and Tfr with rheumatic arthritis[J]. Curr Immunol,2017,37(2):170-173,169.
[7] Vinuesa CG,Tangye SG,Moser B,et al. Follicular B helper T cells in antibody responses and autoimmunity[J]. Nat Rev Immunol,2005,5(11):853-865.
[8] Jogdand GM,Mohanty S,Devadas S. Regulators of Tfh cell differentiation[J]. Front Immunol,2016,7:520.
[9] Nurieva RI,Chung Y,Martinez GJ,et al. Bcl6 mediates the development of T follicular helper cells[J]. Science,2009,325(5943):1001-1005.
[10] Kim CH,Lim HW,Kim JR,et al. Unique gene expression program of human germinal center T helper cells[J]. Blood,2004,104(7):1952-1960.
[11]王文慧,李海滨,宋玉国.乳腺癌患者细胞免疫指标的检测及意义[J].北华大学学报(自然科学版),2017,18(1):53-56.Wang WH,Li HB,Song YG. Detection on cellular immunity and clinical significance in patients with breast cancer[J]. J Beihua Univ(Nat Sci),2017,18(1):53-56.
[12]但刚,刘晨霞,吴丽娟. T淋巴细胞功能及检测方法[J].国际检验医学杂志,2015,36(3):377-380.Dan G,Liu CX,Wu LJ. Function and detection methods on T lymphocytes[J]. Int J Lab Med,2015,36(3):377-380.
[13] Gu-Trantien C,Migliori E,Buisseret L,et al. CXCL13-producing TFH cells link immune suppression and adaptive memory in human breast cancer[J]. JCI Insight,2017,2(11):e91487.
[14] Varricchi G,Harker J,Borriello F,et al. T follicular helper(Tfh)cells in normal immune responses and in allergic disorders[J].Allergy,2016,71(8):1086-1094.
[15] Faghih Z,Erfani N,Haghshenas M R,et al. Immune profiles of CD4+lymphocyte subsets in breast cancer tumor draining lymph nodes[J]. Immunol Lett,2014,158(1-2):57-65.
[16] Kamphorst AO,Wieland A,Nasti T,et al. Rescue of exhausted CD8 T cells by PD-1-targeted therapies is CD28-dependent[J].Science,2017,355(6332):1423-1427.
[17] Callahan MK,Postow MA,Wolchok JD. Targeting T cell coreceptors for cancer therapy[J]. Immunity,2016,44(5):1069-1078.
[18] Pauken KE,Wherry EJ. Overcoming T cell exhaustion in infection and cancer[J]. Trends Immunol,2015,36(4):265-276.
[19] Page DB,Postow MA,Callahan MK,et al. Immune modulation in cancer with antibodies[J]. Annu Rev Med,2014,65:185-202.
[20] Sun S,Fei X,Mao Y,et al. PD-1(+)immune cell infiltration inversely correlates with survival of operable breast cancer patients[J]. Cancer Immunol Immunother,2014,63(4):395-406.
[21] Zhu S,Lin J,Qiao G,et al. Tim-3 identifies exhausted follicular helper T cells in breast cancer patients[J]. Immunobiology,2016,221(9):986-993.
[22] Gu-Trantien C,Loi S,Garaud S,et al. CD4(+)follicular helper T cell infiltration predicts breast cancer survival[J]. J Clin Invest,2013,123(7):2873-2892.
[23] Wollenberg I,Agua-Doce A,Hernandez A,et al. Regulation of the germinal center reaction by Foxp3+follicular regulatory T cells[J]. J Immunol,2011,187(9):4553-4560.
[24] Linterman MA,Pierson W,Lee SK,et al. Foxp3+follicular regulatory T cells control the germinal center response[J]. Nat Med,2011,17(8):975-982.
[25] Jiang BC,Cao DL,Zhang X,et al. CXCL13 drives spinal astrocyte activation and neuropathic pain via CXCR5[J]. J Clin Invest,2016,126(2):745-761.
[26] Grimbacher B,Hutloff A,Schlesier M,et al. Homozygous loss of ICOS is associated with adult-onset common variable immunodeficiency[J]. Nat Immunol,2003,4(3):261-268.
[27] Warnatz K,Bossaller L,Salzer U,et al. Human ICOS deficiency abrogates the germinal center reaction and provides a monogenic model for common variable immunodeficiency[J]. Blood,2006,107(8):3045-3052.
[28] Bauquet AT,Jin H,Paterson AM,et al. The costimulatory molecule ICOS regulates the expression of c-Maf and IL-21 in the development of follicular T helper cells and TH-17 cells[J]. Nat Immunol,2009,10(2):167-175.
[29] Hu H,Wu X,Jin W,et al. Noncanonical NF-kappaB regulates inducible costimulator(ICOS)ligand expression and T follicular helper cell development[J]. Proc Natl Acad Sci U S A,2011,108(31):12827-12832.
[30] Crotty S. T follicular helper cell differentiation,function,and roles in disease[J]. Immunity,2014,41(4):529-542.
[31]陈琦君,白国辉,董竞男,等.转录因子与Tfh细胞分化的研究进展[J].现代免疫学,2015,35(1):63-67.Chen QJ,Bai GH,Dong JN,et al. Recent progress in transcription factors and cell differentiation[J]. Curr Immunol,2015,35(1):63-67.
[32] Crotty S,Johnston RJ,Schoenberger SP. Effectors and memories:Bcl-6 and Blimp-1 in T and B lymphocyte differentiation[J]. Nat Immunol,2010,11(2):114-120.
[33] Winstead CJ,Weaver CT. Dwelling on T cell fate decisions[J].Cell,2013,153(4):739-741.
[34] Sopel N,Graser A,Mousset S,et al. The transcription factor BATF modulates cytokine-mediated responses in T cells[J]. Cytokine Growth Factor Rev,2016,30:39-45.
[35] Mcdonald PW,Read KA,Baker CE,et al. IL-7 signalling represses Bcl-6 and the TFH gene program[J]. Nat Commun,2016,7:10285.
[36] Mathew R,Mao AP,Chiang AH,et al. A negative feedback loop mediated by the Bcl6-cullin 3 complex limits Tfh cell differentiation[J]. J Exp Med,2014,211(6):1137-1151.
[37]冯俊燕,牛俊奇,姜艳芳.滤泡性辅助性T细胞(Tfh)的研究进展[J].中国免疫学杂志,2010,26(8):754-757.Feng JY,Niu JQ,Jiang YF. Recent progress in study on T follicular helper cells(Tfh)[J]. Chin J Immunol,2010,26(8):754-757.
[38] Zotos D,Coquet JM,Zhang Y,et al. IL-21 regulates germinal center B cell differentiation and proliferation through a B cellintrinsic mechanism[J]. J Exp Med,2010,207(2):365-378.
[39] Kwon H,Thierry-Mieg D,Thierry-Mieg J,et al. Analysis of interleukin-21-induced Prdm1 gene regulation reveals functional cooperation of STAT3 and IRF4 transcription factors[J].Immunity,2009,31(6):941-952.
[40] Weinstein JS,Herman EI,Lainez B,et al. TFH cells progressively differentiate to regulate the germinal center response[J]. Nat Immunol,2016,17(10):1197-1205.
[41] Mcguire H M,Vogelzang A,Warren J,et al. IL-21 and IL-4collaborate to shape T-dependent antibody responses[J]. J Immunol,2015,195(11):5123-5135.