人树突状细胞亚群在抗肿瘤免疫中的作用
The Role of Human Dendritic Cell Subsets in Antitumor Immunity

作者: 马莉莉 , 程春来 :长江航运总医院肿瘤科,湖北 武汉; 谷飞飞 :华中科技大学同济医学院附属协和医院肿瘤中心,湖北 武汉;

关键词: 树突状细胞抗肿瘤免疫免疫应答抗原递呈细胞肿瘤Dendritic Cell Antitumor Immunity Immune Responses Antigen Presenting Cells Tumor

摘要: 树突状细胞是人体功能最强大的抗原递呈细胞,在诱导和调控机体针对病原体、自身抗原和癌症的免疫应答中发挥关键作用。树突状细胞是一群异质性细胞,不同的亚群具有独特的表型和功能。基于单核细胞来源的树突状细胞的治疗性疫苗在恶性肿瘤的治疗中显示出一定的疗效,其他树突状细胞亚群在抗肿瘤免疫中也发挥着重要作用。目前,还没有文献对不同树突状细胞亚群在抗肿瘤免疫中的作用进行系统性地阐述。为此,我们对人树突状细胞亚群的生物学特征及其在抗肿瘤免疫中的作用进行综述。

Abstract: Dendritic cells (DCs) are the most potent antigen presenting cells (APC) and critical regulators of immune responses. They play a key role in initiating and regulating the immune responses to pathogens, self-antigens, and cancers. DCs are heterogeneous and highly specialized antigen-presenting cells. Monocyte-derived DCs (MoDC) based therapeutic vaccines have been applied in the treatment of malignancies and showed certain efficacy. And the other dendritic cell subsets also play an important role in antitumor immunity. However, there is no literature that summarizes the roles of different dendritic cell subsets in antitumor immunity until now. Therefore, we reviewed the biological characteristics of human dendritic cell subsets and their roles in antitumor immunity.

1. 引言

抗肿瘤免疫治疗的发展是一个缓慢而艰辛的过程。1777年,外科医生James Nooth给自己注射癌变组织试图控制癌症进展,尽管失败了,这是已知最早的免疫抗癌尝试 [1]。1891年,William Coley发现给肉瘤患者注射链球菌制剂能促进肉瘤体积缩小,并推断是由于细菌制剂诱导了抗肿瘤免疫。以此为起点癌症免疫治疗正式开始,William Coley也常被人们称为“免疫治疗之父” [2]。利用免疫系统治疗癌症的设想已经出现了两百多年,但直到近几年才真正成为癌症治疗的主流方案。以免疫检查点抑制剂为代表的新型免疫疗法开始应用于临床,癌症免疫治疗因此被评为2013年的十大科学突破之首 [3]。

1973年,Ralph Steinman和Zanvil Cohn首次在小鼠脾脏中发现并命名了树突状细胞(Dendritic cell, DC) [4]。DC是人体功能最强大的抗原递呈细胞,免疫应答和免疫耐受的主要调控者,还是沟通先天性免疫和适应性免疫的桥梁。以DC作为疫苗治疗病原体感染与肿瘤,或抑制DC的功能治疗自身免疫性疾病的治疗方案被广泛探索。

2. 人树突状细胞的生物学特性

DC起源于骨髓中的造血祖细胞,是抗原递呈细胞中较少的一个种群 [5]。人树突状细胞主要由外周血DC亚群、皮肤DC亚群和炎性DC亚群组成;此外,还包括单核细胞和CD34+造血祖细胞经体外诱导分化而成的DC亚群。作为专职抗原递呈细胞,DC能调控免疫耐受与免疫应答,在免疫系统中处于中心位置。此外,DC还能与NK细胞、吞噬细胞和肥大细胞等先天免疫系统的免疫细胞发生相互作用,进而调节免疫反应 [6] [7] [8]。DC在体液免疫的调控中也发挥着重要作用,这种调控是通过与B细胞相互作用实现的 [9] [10] [11] [12] [13]。

DC分布于外周组织,它们不断的“检查”这些组织以发现并捕获抗原。DC捕获抗原后将其加工成可被T细胞受体(T cell receptor, TCR)识别的多肽,并表达于细胞表面的抗原递呈分子上。负载抗原之后的DC通过引流淋巴管由组织迁移到引流淋巴结,并借助经典抗原递呈分子(MHC I和MHC II)和非经典抗原递呈分子(CD1家族)将其加工过的蛋白或脂质抗原递呈给T细胞。可溶性抗原也通过淋巴管到达引流淋巴结,被淋巴结内定居的DC递呈。在此过程中DC由未成熟状态转化为成熟状态,获得启动抗原特异性免疫应答的能力,诱导T细胞增殖并分化成具有独特功能和细胞因子分泌谱的辅助和效应细胞。

通常情况下,体内绝大数的DC都处于未成熟状态 [14]。未成熟DC低表达共刺激分子,分泌细胞因子能力不足,活化T细胞的能力较弱,但摄取抗原的能力更强 [15]。未成熟DC能向T细胞递呈自体抗原,通过清除T细胞或诱导调节性T细胞(Regulatory T, Treg)分化而诱导免疫耐受 [16],是中枢免疫耐受和外周免疫耐受所必需的 [17]。未成熟DC对环境中的信号做出应答后分化为成熟DC,其抗原摄取能力下降,但MHC II分子和共刺激分子表达上调,同时细胞因子分泌能力增强 [15]。负载抗原的成熟DC能诱导CD4+T细胞能分化成Th1、Th2、Th17、Tfh或Treg细胞,CD8+T细胞分化成细胞毒性T淋巴细胞,从而诱导免疫应答。T细胞应答的类型取决于递呈抗原的DC亚群。各种DC在受到不同微生物或免疫细胞提供的不同信号刺激后获得独特表型,最终诱导不同的免疫应答。

3. 人树突状细胞亚群与抗肿瘤免疫

3.1. Sipuleucel-T

Sipuleucel-T (APC8015,商品名Provenge)是目前所知的第一个且唯一的一个以DC为基础的高级治疗性疫苗,被FDA批准用于治疗转移性且激素抵抗的前列腺癌 [18]。Sipuleucel-T是由多种抗原递呈细胞组成的疫苗,包含了血液中的所有DC亚群、B细胞和单核细胞等。疫苗的制备从获得大量自体PBMC开始,将PBMC与PA2024在体外培养36~44个小时。PA2024是一种融合蛋白,由肿瘤抗原前列腺酸性磷酸酶与免疫刺激细胞因子GM-CSF构成。经过以上同步抗原负载和激活步骤后,清洗并悬浮这些细胞,然后通过静脉回输给患者。在一项III期临床试验中,Sipuleucel-T将转移性激素抵抗的前列腺癌患者的总生存期延长了4.1个月 [19]。

3.2. MoDC

血液中自然生成的DC数量极少,很难获得足够数量的DC用于免疫治疗。因此,多数临床研究通过体外诱导生成大量的DC来实现免疫治疗的目的,被诱导分化成DC的起始细胞通常是单核细胞和CD34+造血祖细胞 [20]。以DC为基础的治疗性疫苗绝大多数树是单核细胞经体外刺激而分化成的DC,即单核细胞源性树突状细胞(monocyte derived dendritic cell, MoDC) [13] [20]。到目前为止,MoDC仍然是构建DC疫苗最常用的DC类型 [21] [22]。MoDC,尤其是IL-15诱导分化的MoDC能高效地将黑色素瘤特异性CD8+T细胞活化成CTL,从而在抗黑色素瘤免疫应答中发挥重要作用 [23] [24]。

3.3. 人外周血DC亚群

血液DC约占PBMC总数的1% [25],根据造血细胞来源可分为两群:髓系DC(mDC,亦称经典DC,髓系)和浆细胞样DC (pDC,淋系) [20] [26]。髓系DC以表达CD11C为特征,根据表面分子表达差异又可分成三个不同亚群:CD141+(BDCA3) DC、CD16+DC和CD1c+(BDCA1) DC [25] [27] [28]。CD141+DC是人外周血中数量最少的DC亚群,仅占PBMC总数的0.05%左右 [25] [29]。未成熟CD141+DC特异性表达C型凝集素受体CLEC9A,还表达toll样受体(Tolllikereceptor, TLR)如TLR1、TLR2、TLR3、TLR6、TLR8和TLR10;前者介导人CD141+DC对抗原的摄取和(交叉)递呈,后者刺激DC成熟 [18] [21]。人CD141+DC与小鼠CD8α+DC有很多相似的表型,两者都表达TLR3、Necl2 (Nectin-like protein2)和CLEC9A [30] [31] [32] [33] [34]。因此,有学者认为人CD141+DC与小鼠CD8α+DC相对应,二者具有类似的功能特性。然而,值得注意的是人鼠DC之间还有很大的差异,如小鼠的mDC表达TLR9并分泌干扰素-α (Interferonα, IFN-α) [35] [36],而在人身上这些是pDC独有的特征 [37],其次是人的DC都不表达CD8α。CD16+DC与CD1c+DC均表达TLR1、TLR2、TLR4、TLR5、TLR6、TLR8、TLR9和TLR10,CD1c+DC还表达TLR3 [38]。这两种DC亚群经TLR激动剂刺激后都能分泌CXCL8 (IL-8)、TNF-α、IL-6、CCL3 (MIP-1α)、CCL4 (MIP-1β)、IL-1β,其中CD1c+ DC主要分泌CXCL8 (IL-8),CD16+DC分泌的TNF-α量远远超过CD1c+DC [22]。CD16+DC具有很强的促炎能力,而CD1c+DC似乎主要诱导趋化作用。pDC在血液中循环,通过高内皮静脉进入淋巴器官 [39]。pDC不表达CD11C,高表达IL-3Rα链(CD123),还特异性表达BDCA2 (CD303)、ILT7和BDCA4 (CD304) [40]。pDC通过TLR7和(或) TLR9识别病毒片段后被激活,分泌大量I型IFN [39]。pDC接触病毒后能诱导抗病毒T细胞免疫应答 [41] [42],从而在抗病毒免疫中发挥重要作用。

探索各DC亚群在抗肿瘤免疫应答中的作用的研究主要集中于免疫原较强的黑色素瘤。CD141+DC、CD1c+DC、CD16+DC和pDC都能摄取、加工可溶性黑色素瘤抗原,并向特异性CD8+T细胞交叉递呈处理后的抗原表位肽,从而激活CTL发挥抗肿瘤作用 [27] [43] [44]。尽管摄取黑色素瘤抗原的能力弱于CD141+DC、CD1c+DC及CD16+DC,pDC能更有效地向CD8+T细胞交叉递呈源于黑色素瘤细胞裂解产物的抗原 [47]。考虑到外周血中pDC的数量远远超过CD141+DC,在交叉递呈肿瘤细胞来源的抗原时pDC至少拥有不弱于CD141+DC的能力。

3.4. 皮肤DC亚群

皮肤DC主要包括两个亚群:表皮朗格汉斯细胞(LC)和真皮DC,真皮DC又分为两个亚群:CD1a+DC和CD14+DC [19]。朗格汉斯细胞以表达CD1a和CD207为特征,还表达TLR1、TLR2、TLR3、TLR6及TLR10,通过分泌IL-15而有效地将CD8+T细胞活化成CTL [20] [24] [26]。朗格汉斯细胞经CD40-CD40L通路活化后,仅分泌少量细胞因子,包括IL-15和IL-8;朗格汉斯细胞倾向于诱导CD4+T细胞分泌Th2型细胞因子,但能有效地将naïve CD8+T细胞活化成CTL [45]。CD14+DC表达很多C型凝集素和TLRs,前者包括DC-SIGN、DEC205、LOX-1、CLEC-6及DCIR,后者主要是TLR2、TLR4、TLR5、TLR6、TLR8及TLR10 [26]。CD14+DC经CD40-CD40L通路活化后,分泌大量细胞因子,包括IL-1β、IL-6、IL-8、IL-10、IL-12p40、GM-CSF、MCP-1及TNF-α [38]。CD14+DC极化naïve CD4+T细胞向滤泡辅助性T细胞分化,后者诱导naïve B细胞发生表型转化并分化成浆细胞,从而促进体液免疫的发生 [38]。CD1a+DC表达CD1c,其表型与朗格汉斯细胞接近,但不表达朗格汉斯细胞特征性分子CD207和E-钙粘蛋白。CD1a+DC激活CD8+T细胞的能力优于CD14+DC而弱于朗格汉斯细胞,经CD40L激活后分泌大量的IL-15和IL-8 [38],与朗格汉斯细胞类似。CD1a+DC可能是朗格汉斯细胞的前体细胞。表皮朗格汉斯细胞分泌的细胞因子主要是IL-15 [38]。朗格汉斯细胞递呈可溶性黑素瘤抗原的能力更强且能有效地促进抗黑色素瘤效应CTL产生 [37] [38],CD14+DC分泌IL-10和TGF-β抑制抗黑色瘤效应CTL的形成 [37]。

3.5. 炎性树突状细胞

在炎症时,机体内出现了一种新型DC,即炎性DC。炎性DC由募集到炎症部位的单核细胞分化而成 [46],人的炎性DC首次发现于卵巢癌和乳腺癌患者的腹腔积液中,它们也出现于非肿瘤性炎性积液中 [32]。人的炎性DC表达TLR1、TLR2、TLR3、TLR4、TLR5、TLR6、TLR7、TLR8、TLR9及TLR10,但不表达DC-SIGN [32]。人的炎性DC通过分泌IL-23等细胞因子诱导自体记忆性CD4+T细胞及异基因naïve CD4+T细胞分化成Th17型细胞 [20],Th17型细胞在肿瘤免疫中兼具抗肿瘤与促肿瘤作用 [47] [48] [49] [50]。

4. 结论

DC的发现在免疫学发展史上具有划时代的意义,其发现者Ralph Steinman因此获得了2011年的诺贝尔生理学或医学奖。尽管探索DC免疫学功能的研究之路坎坷不平,在DC发现四十余年后人们对DC在免疫中发挥的作用有了深入的了解。目前,人们对DC在免疫原性较强的黑色素瘤等肿瘤中的作用有了一定的认识。然而,在肺癌等免疫原性差的肿瘤中,DC在抗肿瘤免疫中发挥的作用尚不十分清晰。未来的研究需要继续探索各种DC亚群在不同肿瘤免疫应答中的作用,这将有利于设计更有效的DC疫苗,为根治肿瘤带来希望。

文章引用: 马莉莉 , 程春来 , 谷飞飞 (2020) 人树突状细胞亚群在抗肿瘤免疫中的作用。 临床医学进展, 10, 232-238. doi: 10.12677/ACM.2020.103037

参考文献

[1] Rosenberg, S.A. (1999) A New Era for Cancer Immunotherapy Based on the Genes That Encode Cancer Antigens. Immunity, 10, 281-287.
https://doi.org/10.1016/S1074-7613(00)80028-X

[2] Coley, W.B. (1891) II. Contribution to the Knowledge of Sarcoma. Annals of Surgery, 14, 199-220.
https://doi.org/10.1097/00000658-189112000-00015

[3] Couzin-Frankel, J. (2013) Breakthrough of the Year 2013. Cancer Immunotherapy. Science, 342, 1432-1433.
https://doi.org/10.1126/science.342.6165.1432

[4] Steinman, R.M. and Cohn, Z.A. (1973) Identification of a Novel Cell Type in Peripheral Lymphoid Organs of Mice. I. Morphology, Quantitation, Tissue Distribution. Journal of Experimental Medicine, 137, 1142-1162.
https://doi.org/10.1084/jem.137.5.1142

[5] Collin, M., McGovern, N. and Haniffa, M. (2013) Human Dendritic Cell Subsets. Immunology, 140, 22-30.
https://doi.org/10.1111/imm.12117

[6] Banchereau, J. and Steinman, R.M. (1998) Dendritic Cells and the Control of Immunity. Nature, 392, 245-252.
https://doi.org/10.1038/32588

[7] Steinman, R.M. and Banchereau, J. (2007) Taking Dendritic Cells into Medicine. Nature, 449, 419-426.
https://doi.org/10.1038/nature06175

[8] Steinman, R.M. (2012) Decisions about Dendritic Cells: Past, Present, and Future. Annual Review of Immunology, 30, 1-22.
https://doi.org/10.1146/annurev-immunol-100311-102839

[9] Jego, G., Pascual, V., Palucka, A.K. and Banchereau, J. (2005) Dendritic Cells Control B Cell Growth and Differentiation. Current Directions in Autoimmunity, 8, 124-139.
https://doi.org/10.1159/000082101

[10] Qi, H., Egen, J.G., Huang, A.Y. and Germain, R.N. (2006) Extrafollicular Activation of Lymph Node B Cells by Antigen-Bearing Dendritic Cells. Science, 312, 1672-1676.
https://doi.org/10.1126/science.1125703

[11] Batista, F.D. and Harwood, N.E. (2009) The Who, How and Where of Antigen Presentation to B Cells. Nature Reviews Immunology, 9, 15-27.
https://doi.org/10.1038/nri2454

[12] Bergtold, A., Desai, D.D., Gavhane, A. and Clynes, R. (2005) Cell Surface Recycling of Internalized Antigen Permits Dendritic Cell Priming of B Cells. Immunity, 23, 503-514.
https://doi.org/10.1016/j.immuni.2005.09.013

[13] Palucka, K. and Banchereau, J. (2012) Cancer Immunotherapy via Dendritic Cells. Nature Reviews Cancer, 12, 265-277.
https://doi.org/10.1038/nrc3258

[14] Wilson, N.S., El-Sukkari, D., Belz, G.T., Smith, C.M., Steptoe, R.J., et al. (2003) Most Lymphoid Organ Dendritic Cell Types Are Phenotypically and Functionally Immature. Blood, 102, 2187-2194.
https://doi.org/10.1182/blood-2003-02-0513

[15] Trombetta, E.S. and Mellman, I. (2005) Cell Biology of Antigen Processing in Vitro and in Vivo. Annual Review of Immunology, 23, 975-1028.
https://doi.org/10.1146/annurev.immunol.22.012703.104538

[16] Heath, W.R. and Carbone, F.R. (2001) Cross-Presentation, Dendritic Cells, Tolerance and Immunity. Annual Review of Immunology, 19, 47-64.
https://doi.org/10.1146/annurev.immunol.19.1.47

[17] Liu, Y.J., Soumelis, V., Watanabe, N., Ito, T., Wang, Y.H., et al. (2007) TSLP: An Epithelial Cell Cytokine That Regulates T Cell Differentiation by Conditioning Dendritic Cell Maturation. Annual Review of Immunology, 25, 193-219.
https://doi.org/10.1146/annurev.immunol.25.022106.141718

[18] Melero, I., Gaudernack, G., Gerritsen, W., Huber, C., Parmiani, G., et al. (2014) Therapeutic Vaccines for Cancer: An Overview of Clinical Trials. Nature Reviews Clinical Oncology, 11, 509-524.
https://doi.org/10.1038/nrclinonc.2014.111

[19] Kantoff, P.W., Higano, C.S., Shore, N.D., Berger, E.R., Small, E.J., et al. (2010) Sipuleucel-T Immunotherapy for Castration-Resistant Prostate Cancer. The New England Journal of Medicine, 363, 411-422.
https://doi.org/10.1056/NEJMoa1001294

[20] Anguille, S., Smits, E.L., Bryant, C., Van Acker, H.H., Goossens, H., et al. (2015) Dendritic Cells as Pharmacological Tools for Cancer Immunotherapy. Pharmacological Reviews, 67, 731-753.
https://doi.org/10.1124/pr.114.009456

[21] Anguille, S., Smits, E.L., Lion, E., van Tendeloo, V.F. and Berneman, Z.N. (2014) Clinical Use of Dendritic Cells for Cancer Therapy. The Lancet Oncology, 15, e257-e267.
https://doi.org/10.1016/S1470-2045(13)70585-0

[22] Chiang, C.L., Balint, K., Coukos, G. and Kandalaft, L.E. (2015) Potential Approaches for More Successful Dendritic Cell-Based Immunotherapy. Expert Opinion on Biological Therapy, 15, 569-582.
https://doi.org/10.1517/14712598.2015.1000298

[23] Mohamadzadeh, M., Berard, F., Essert, G., Chalouni, C., Pulendran, B., et al. (2001) Interleukin 15 Skews Monocyte Differentiation into Dendritic Cells with Features of Langer-hans Cells. Journal of Experimental Medicine, 194, 1013-1020.
https://doi.org/10.1084/jem.194.7.1013

[24] Dubsky, P., Saito, H., Leogier, M., Dantin, C., Connolly, J.E., et al. (2007) IL-15-Induced Human DC Efficiently Prime Melanoma-Specific Naive CD8+ T Cells to Differentiate into CTL. European Journal of Immunology, 37, 1678-1690.
https://doi.org/10.1002/eji.200636329

[25] Jongbloed, S.L., Kassianos, A.J., McDonald, K.J., Clark, G.J., Ju, X., et al. (2010) Human CD141+ (BDCA-3)+ Dendritic Cells (DCs) Represent a Unique Myeloid DC Subset That Cross-Presents Necrotic Cell Antigens. Journal of Experimental Medicine, 207, 1247-1260.
https://doi.org/10.1084/jem.20092140

[26] Ueno, H., Klechevsky, E., Schmitt, N., Ni, L., Flamar, A.L., et al. (2011) Targeting Human Dendritic Cell Subsets for Improved Vaccines. Seminars in Immunology, 23, 21-27.
https://doi.org/10.1016/j.smim.2011.01.004

[27] Schreibelt, G., Klinkenberg, L.J., Cruz, L.J., Tacken, P.J., Tel, J., et al. (2012) The C-Type Lectin Receptor CLEC9A Mediates Antigen Uptake and (Cross-)presentation by Human Blood BDCA3+ Myeloid Dendritic Cells. Blood, 119, 2284-2292.
https://doi.org/10.1182/blood-2011-08-373944

[28] Piccioli, D., Tavarini, S., Borgogni, E., Steri, V., Nuti, S., et al. (2007) Functional Specialization of Human Circulating CD16 and CD1c Myeloid Dendritic-Cell Subsets. Blood, 109, 5371-5379.
https://doi.org/10.1182/blood-2006-08-038422

[29] Alculumbre, S. and Pattarini, L. (2016) Purification of Human Dendritic Cell Subsets from Peripheral Blood. Methods in Molecular Biology, 1423, 153-167.
https://doi.org/10.1007/978-1-4939-3606-9_11

[30] Lindstedt, M., Lundberg, K. and Borrebaeck, C.A. (2005) Gene Family Clustering Identifies Functionally Associated Subsets of Human in Vivo Blood and Tonsillar Dendritic Cells. The Journal of Immunology, 175, 4839-4846.
https://doi.org/10.4049/jimmunol.175.8.4839

[31] Edwards, A.D., Diebold, S.S., Slack, E.M., Tomizawa, H., Hemmi, H., et al. (2003) Toll-Like Receptor Expression in Murine DC Subsets: Lack of TLR7 Expression by CD8 Alpha+ DC Correlates with Unresponsiveness to Imidazoquinolines. European Journal of Immunology, 33, 827-833.
https://doi.org/10.1002/eji.200323797

[32] Galibert, L., Diemer, G.S., Liu, Z., Johnson, R.S., Smith, J.L., et al. (2005) Nectin-Like Protein 2 Defines a Subset of T-Cell Zone Dendritic Cells and Is a Ligand for Class-I-Restricted T-Cell-Associated Molecule. The Journal of Biological Chemistry, 280, 21955-21964.
https://doi.org/10.1074/jbc.M502095200

[33] Huysamen, C., Willment, J.A., Dennehy, K.M. and Brown, G.D. (2008) CLEC9A Is a Novel Activation C-Type Lectin-Like Receptor Expressed on BDCA3+ Dendritic Cells and a Subset of Monocytes. The Journal of Biological Chemistry, 283, 16693-16701.
https://doi.org/10.1074/jbc.M709923200

[34] Sancho, D., Mourao-Sa, D., Joffre, O.P., Schulz, O., Rogers, N.C., et al. (2008) Tumor Therapy in Mice via Antigen Targeting to a Novel, DC-Restricted C-Type Lectin. Journal of Clinical Investigation, 118, 2098-2110.
https://doi.org/10.1172/JCI34584

[35] Poulin, L.F., Salio, M., Griessinger, E., Anjos-Afonso, F., Craciun, L., et al. (2010) Characterization of Human DNGR-1+ BDCA3+ Leukocytes as Putative Equivalents of Mouse CD8alpha+ Dendritic Cells. Journal of Experimental Medicine, 207, 1261-1271.
https://doi.org/10.1084/jem.20092618

[36] Hochrein, H., Shortman, K., Vremec, D., Scott, B., Hertzog, P., et al. (2001) Differential Production of IL-12, IFN-Alpha, and IFN-Gamma by Mouse Dendritic Cell Subsets. The Journal of Immunology, 166, 5448-5455.
https://doi.org/10.4049/jimmunol.166.9.5448

[37] Jarrossay, D., Napolitani, G., Colonna, M., Sallusto, F. and Lanzavecchia, A. (2001) Specialization and Complementarity in Microbial Molecule Recognition by Human Myeloid and Plasmacytoid Dendritic Cells. European Journal of Immunology, 31, 3388-3393.
https://doi.org/10.1002/1521-4141(200111)31:11<3388::AID-IMMU3388>3.0.CO;2-Q

[38] Segura, E., Touzot, M., Bohineust, A., Cappuccio, A., Chiocchia, G., et al. (2013) Human Inflammatory Dendritic Cells Induce Th17 Cell Differentiation. Immunity, 38, 336-348.
https://doi.org/10.1016/j.immuni.2012.10.018

[39] Siegal, F.P., Kadowaki, N., Shodell, M., Fitzgerald-Bocarsly, P.A., Shah, K., et al. (1999) The Nature of the Principal Type 1 Inter-feron-Producing Cells in Human Blood. Science, 284, 1835-1837.
https://doi.org/10.1126/science.284.5421.1835

[40] Cao, W., Rosen, D.B., Ito, T., Bover, L., Bao, M., et al. (2006) Plasmacytoid Dendritic Cell-Specific Receptor ILT7-Fc epsilonRI Gamma Inhibits Toll-Like Receptor-Induced Interferon Production. Journal of Experimental Medicine, 203, 1399-1405.
https://doi.org/10.1084/jem.20052454

[41] Di Pucchio, T., Chatterjee, B., Smed-Sorensen, A., Clayton, S., Palazzo, A., et al. (2008) Direct Proteasome-Independent Cross-Presentation of Viral Antigen by Plasmacytoid Dendritic Cells on Major Histocompatibility Complex Class I. Nature Immunology, 9, 551-557.
https://doi.org/10.1038/ni.1602

[42] Fonteneau, J.F., Gilliet, M., Larsson, M., Dasilva, I., Munz, C., et al. (2003) Activation of Influenza Virus-Specific CD4+ and CD8+ T Cells: A New Role for Plasmacytoid Dendritic Cells in Adaptive Immunity. Blood, 101, 3520-3526.
https://doi.org/10.1182/blood-2002-10-3063

[43] Tel, J., Schreibelt, G., Sittig, S.P., Mathan, T.S., Buschow, S.I., et al. (2013) Human Plasmacytoid Dendritic Cells Efficiently Cross-Present Exogenous Ags to CD8+ T Cells Despite Lower Ag Uptake than Myeloid Dendritic Cell Subsets. Blood, 121, 459-467.
https://doi.org/10.1182/blood-2012-06-435644

[44] Banchereau, J., Thompson-Snipes, L., Zurawski, S., Blanck, J.P., Cao, Y., et al. (2012) The Differential Production of Cytokines by Human Langerhans Cells and Dermal CD14(+) DCs Controls CTL Priming. Blood, 119, 5742-5749.
https://doi.org/10.1182/blood-2011-08-371245

[45] Klechevsky, E., Morita, R., Liu, M., Cao, Y., Coquery, S., et al. (2008) Functional Specializations of Human Epidermal Langerhans Cells and CD14+ Dermal Dendritic Cells. Im-munity, 29, 497-510.
https://doi.org/10.1016/j.immuni.2008.07.013

[46] Leon, B., Lopez-Bravo, M. and Ardavin, C. (2007) Mono-cyte-Derived Dendritic Cells Formed at the Infection Site Control the Induction of Protective T Helper 1 Responses against Leishmania. Immunity, 26, 519-531.
https://doi.org/10.1016/j.immuni.2007.01.017

[47] Zou, W. and Restifo, N.P. (2010) T(H)17 Cells in Tumour Immunity and Immunotherapy. Nature Reviews Immunology, 10, 248-256.
https://doi.org/10.1038/nri2742

[48] Muranski, P. and Restifo, N.P. (2009) Does IL-17 Promote Tumor Growth? Blood, 114, 231-232.
https://doi.org/10.1182/blood-2009-04-215541

[49] Munn, D.H. (2009) Th17 Cells in Ovarian Cancer. Blood, 114, 1134-1135.
https://doi.org/10.1182/blood-2009-06-224246

[50] Bronte, V. (2008) Th17 and Cancer: Friends or Foes? Blood, 112, 214.
https://doi.org/10.1182/blood-2008-04-149260

分享
Top