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Article(id=1226236832401240671, tenantId=1146029695717560320, journalId=1192105938417971205, issueId=1226236828399878330, articleNumber=null, orderNo=null, doi=10.13343/j.cnki.wsxb.20240678, pmid=null, cstr=null, oa=null, hot=null, price=null, onlineType=0, articleFormat=0, articleType=null, articleTypeStr=research-article, receivedDate=1730476800000, receivedDateStr=2024-11-02, revisedDate=null, revisedDateStr=null, acceptedDate=1739030400000, acceptedDateStr=2025-02-09, onlineDate=1770287243222, onlineDateStr=2026-02-05, pubDate=1746288000000, pubDateStr=2025-05-04, doiRegisterDate=null, doiRegisterDateStr=null, onlineIssueDate=1770287243222, onlineIssueDateStr=2026-02-05, onlineJustAcceptDate=null, onlineJustAcceptDateStr=null, onlineFirstDate=null, onlineFirstDateStr=null, sourceXml=null, magXml=null, createTime=1770287243222, creator=13701087609, updateTime=1770287243222, updator=13701087609, issue=Issue{id=1226236828399878330, tenantId=1146029695717560320, journalId=1192105938417971205, year='2025', volume='65', issue='5', pageStart='1831', pageEnd='2319', issueExtLink='null', onlineDate='null', pubDate='null', beforeIssueId=null, nextIssueId=null, price=null, status=1, issueComplete=1, articleOrder=1, issueType=-1, specialIssue=null, createTime=1770287242269, creator=13701087609, updateTime=1770344517883, updator=13701087609, preIssue=null, nextIssue=null, ext={EN=IssueExt(id=1226477059812274835, tenantId=1146029695717560320, journalId=1192105938417971205, issueId=1226236828399878330, language=EN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=), CN=IssueExt(id=1226477059816469140, tenantId=1146029695717560320, journalId=1192105938417971205, issueId=1226236828399878330, language=CN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=)}, issueFiles=null}, startPage=1905, endPage=1917, ext={EN=ArticleExt(id=1226236833412067963, articleId=1226236832401240671, tenantId=1146029695717560320, journalId=1192105938417971205, language=EN, title=Advances in the molecular mechanisms of Mycobacteriumtuberculosis in regulating antigen presentation in dendritic cells, columnId=1192149543727808575, journalTitle=Acta Microbiologica Sinica, columnName=Review, runingTitle=null, highlight=null, articleAbstract=

Tuberculosis is an ancient zoonotic disease that poses a serious threat to the health of humans and animals worldwide. Mycobacteriumtuberculosis (Mtb) is the primary causative agent of tuberculosis. As a bridge between innate and adaptive immunity, dendritic cells (DCs) play a pivotal role in controlling Mtb infection by utilizing their potent antigen-presenting capacity to activate the adaptive immune response of the host and thus resist further infection. In recent years, more and more studies have shown that Mtb can evade host immune defenses by regulating DC differentiation and maturation, interfering with phagocytosis and autophagy, and inhibiting the expression of antigen presentation-related molecules, thus causing persistent infection. This review summarizes the current research on the molecular mechanisms of Mtb in regulating DC antigen presentation, aiming to provide insights for further study of Mtb-DC interaction mechanism and development of prevention and control strategies for tuberculosis.

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E-mail: CHU Yuefeng,
SONG Yinjuan,
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结核病是一种古老且严重危害全球人类和动物健康的人兽共患病，结核分枝杆菌(Mycobacteriumtuberculosis, Mtb)是引起结核病的主要病原体。树突状细胞(dendritic cell, DC)作为连接机体固有免疫应答和适应性免疫应答的桥梁，凭借其强大的抗原提呈功能激活宿主适应性免疫反应，以抵御病原体的进一步感染，在控制Mtb感染中发挥重要作用。近年来，越来越多的研究表明Mtb可通过调控DC分化和成熟、干扰吞噬作用和自噬过程、抑制抗原提呈相关分子的表达等多种策略逃避宿主免疫杀伤，从而引起持续性感染。本文就目前Mtb调控DC抗原提呈分子机制的研究进展进行梳理，以期为进一步深入研究Mtb-DC互作机制及结核病防控策略提供参考。

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作者贡献声明

马慧：论文撰写及修改；宋银娟：论文思路提出及修改；马玲：部分图表绘制；储岳峰：论文修改与审校。

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articleId=1226236832401240671, language=EN, label=Figure 1, caption=The classical pathways of antigen presentation by dendritic cells. Dendritic cells present antigens to T cells through the proteasome pathway, lysosomal pathway, and cross-presentation., figureFileSmall=wLO1dQL3/eN+yDWghbdmoA==, figureFileBig=6RCZVUK4TBCiLqCkDqd3rA==, tableContent=null), ArticleFig(id=1226592748032144252, tenantId=1146029695717560320, journalId=1192105938417971205, articleId=1226236832401240671, language=CN, label=图1, caption=树突状细胞提呈抗原的经典途径, figureFileSmall=wLO1dQL3/eN+yDWghbdmoA==, figureFileBig=6RCZVUK4TBCiLqCkDqd3rA==, tableContent=null), ArticleFig(id=1226592748174750605, tenantId=1146029695717560320, journalId=1192105938417971205, articleId=1226236832401240671, language=EN, label=Figure 2, caption=The dendritic cell immune response to Mycobacteriumtuberculosis. Mycobacteriumtuberculosis infected DC migrates to the local lung-draining lymph nodes post infection. DC migrates to the lymph nodes under the influence of IL-12(p40)2, IL-12p70, and the chemokines CCL19 and CCL21. This migration facilitates the differentiation of naive T cells into a Th1 phenotype. Subsequently, protective antigen-specific Th1 cells migrate back to the lungs in a chemokine-dependent manner following the initial infection/exposure, where they produce IFN-γ., figureFileSmall=MvlB/JlOM5cmTfN9d8TQ+A==, figureFileBig=QYAg7ivmMgRsNTnpaTUFvg==, tableContent=null), ArticleFig(id=1226592748300579734, tenantId=1146029695717560320, journalId=1192105938417971205, articleId=1226236832401240671, language=CN, label=图2, caption=结核分枝杆菌感染的树突状细胞免疫反应, figureFileSmall=MvlB/JlOM5cmTfN9d8TQ+A==, figureFileBig=QYAg7ivmMgRsNTnpaTUFvg==, tableContent=null), ArticleFig(id=1226592748397048732, tenantId=1146029695717560320, journalId=1192105938417971205, articleId=1226236832401240671, language=EN, label=Figure 3, caption=The mechanism by which Mycobacteriumtuberculosis regulates antigen presentation in dendritic cells., figureFileSmall=Cdqmhzksrb3p5QT+entKow==, figureFileBig=Ca9KVxcWKTpMJjdIpmP7Kg==, tableContent=null), ArticleFig(id=1226592748489323425, tenantId=1146029695717560320, journalId=1192105938417971205, articleId=1226236832401240671, language=CN, label=图3, caption=结核分枝杆菌调控树突状细胞抗原提呈的机制, figureFileSmall=Cdqmhzksrb3p5QT+entKow==, figureFileBig=Ca9KVxcWKTpMJjdIpmP7Kg==, tableContent=null), ArticleFig(id=1226592748623541163, tenantId=1146029695717560320, journalId=1192105938417971205, articleId=1226236832401240671, language=EN, label=Table 1, caption=

Differences in dendritic cell subpopulations

, figureFileSmall=null, figureFileBig=null, tableContent=
TypeDistributionTranscription factorPhenotypeFunctionReferences
cDC1Blood, lymph nodes, tonsils, spleen, bone marrowRet3, Csf2ra, Irf8, Batf3, Bcl6, Id2XCR1, DNGR-1, CD205, CD207Cross-presentation of the antigen to CD8+ T cells, producing high levels of IL-12p70, and promoting activation of cytotoxic T lymphocytes and Th1[12-17]
cDC2Blood, lymp, organs, skin, LungsSfpi1, Zbtb46, Irf4CD11b, CD11c, SIRPαPresenting MHC class II antigens and promoting the differentiation of Th1, Th2, and Th17[16,18-19]
pDC

lymph nodes,

tonsils, peripheral blood

Tcf4, Bcl11a, Runx2, SpiBCD304, CD303, CD123, BDCA2The first line of defense against viral infection, initiating IFN-induced antiviral response, and recruiting cytotoxic NK cells[10,16,20-21]
), ArticleFig(id=1226592748757758901, tenantId=1146029695717560320, journalId=1192105938417971205, articleId=1226236832401240671, language=CN, label=表1, caption=

树突状细胞亚群的差异性

, figureFileSmall=null, figureFileBig=null, tableContent=
TypeDistributionTranscription factorPhenotypeFunctionReferences
cDC1Blood, lymph nodes, tonsils, spleen, bone marrowRet3, Csf2ra, Irf8, Batf3, Bcl6, Id2XCR1, DNGR-1, CD205, CD207Cross-presentation of the antigen to CD8+ T cells, producing high levels of IL-12p70, and promoting activation of cytotoxic T lymphocytes and Th1[12-17]
cDC2Blood, lymp, organs, skin, LungsSfpi1, Zbtb46, Irf4CD11b, CD11c, SIRPαPresenting MHC class II antigens and promoting the differentiation of Th1, Th2, and Th17[16,18-19]
pDC

lymph nodes,

tonsils, peripheral blood

Tcf4, Bcl11a, Runx2, SpiBCD304, CD303, CD123, BDCA2The first line of defense against viral infection, initiating IFN-induced antiviral response, and recruiting cytotoxic NK cells[10,16,20-21]
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结核分枝杆菌调控树突状细胞抗原提呈的分子机制研究进展
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马慧 1 , 宋银娟 1 , 马玲 2 , 储岳峰 1
微生物学报 | 综述 2025,65(5): 1905-1917
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微生物学报 | 综述 2025, 65(5): 1905-1917
结核分枝杆菌调控树突状细胞抗原提呈的分子机制研究进展
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马慧1, 宋银娟1 , 马玲2, 储岳峰1
作者信息
  • 1.中国农业科学院兰州兽医研究所/兰州大学 动物医学与生物安全学院，动物疫病防控全国重点实验室 甘肃 兰州
  • 2.甘肃省疾病预防控制中心 甘肃 兰州
Advances in the molecular mechanisms of Mycobacteriumtuberculosis in regulating antigen presentation in dendritic cells
Hui MA1, Yinjuan SONG1 , Ling MA2, Yuefeng CHU1
Affiliations
  • 1.State Key Laboratory for Animal Disease Control and Prevention, College of Veterinary Medicine, Lanzhou University, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, Gansu, China
  • 2.Gansu Provincial Center for Disease Control and Prevention, Lanzhou, Gansu, China
出版时间: 2025-05-04 doi: 10.13343/j.cnki.wsxb.20240678
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摘要
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结核病是一种古老且严重危害全球人类和动物健康的人兽共患病，结核分枝杆菌(Mycobacteriumtuberculosis, Mtb)是引起结核病的主要病原体。树突状细胞(dendritic cell, DC)作为连接机体固有免疫应答和适应性免疫应答的桥梁，凭借其强大的抗原提呈功能激活宿主适应性免疫反应，以抵御病原体的进一步感染，在控制Mtb感染中发挥重要作用。近年来，越来越多的研究表明Mtb可通过调控DC分化和成熟、干扰吞噬作用和自噬过程、抑制抗原提呈相关分子的表达等多种策略逃避宿主免疫杀伤，从而引起持续性感染。本文就目前Mtb调控DC抗原提呈分子机制的研究进展进行梳理，以期为进一步深入研究Mtb-DC互作机制及结核病防控策略提供参考。

结核分枝杆菌  /  树突状细胞  /  抗原提呈  /  分子机制

Tuberculosis is an ancient zoonotic disease that poses a serious threat to the health of humans and animals worldwide. Mycobacteriumtuberculosis (Mtb) is the primary causative agent of tuberculosis. As a bridge between innate and adaptive immunity, dendritic cells (DCs) play a pivotal role in controlling Mtb infection by utilizing their potent antigen-presenting capacity to activate the adaptive immune response of the host and thus resist further infection. In recent years, more and more studies have shown that Mtb can evade host immune defenses by regulating DC differentiation and maturation, interfering with phagocytosis and autophagy, and inhibiting the expression of antigen presentation-related molecules, thus causing persistent infection. This review summarizes the current research on the molecular mechanisms of Mtb in regulating DC antigen presentation, aiming to provide insights for further study of Mtb-DC interaction mechanism and development of prevention and control strategies for tuberculosis.

Mycobacteriumtuberculosis  /  dendritic cells  /  antigen presentation  /  molecular mechanisms
马慧, 宋银娟, 马玲, 储岳峰. 结核分枝杆菌调控树突状细胞抗原提呈的分子机制研究进展. 微生物学报, 2025 , 65 (5) : 1905 -1917 . DOI: 10.13343/j.cnki.wsxb.20240678
Hui MA, Yinjuan SONG, Ling MA, Yuefeng CHU. Advances in the molecular mechanisms of Mycobacteriumtuberculosis in regulating antigen presentation in dendritic cells[J]. Acta Microbiologica Sinica, 2025 , 65 (5) : 1905 -1917 . DOI: 10.13343/j.cnki.wsxb.20240678
正文
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结核分枝杆菌(Mycobacteriumtuberculosis, Mtb)是一种胞内病原体，主要通过呼吸道感染，引起人和动物的结核病。世界卫生组织发布的《2024年全球结核病报告》显示，2023年全球约有1 080万新发结核病患者，因结核病死亡的人数为125万，结核病重返导致人类死亡的单一传染病之首[1]。在全球30个结核病高负担国家中，我国结核病新发患者数位列第3，2023年估算的结核病新发患者数为74.1万，表明我国结核病的防控仍任重道远[2]。作为引起结核病的主要病原体，Mtb最初特异性地感染肺脏驻留的肺泡巨噬细胞，并通过逃避宿主的免疫应答进行增殖以在细胞内存活[3-4]。
树突状细胞(dendritic cell, DC)最初由加拿大学者Steinman等于1973年在小鼠脾脏中发现，因成熟时有许多树枝状或伪足样突起而得名[5]。目前，人们广泛认为DC是机体功能最强的专职抗原提呈细胞，它能高效地摄取、加工、处理和提呈抗原。因此，DC被认为是机体适应性免疫应答的启动者，是连接固有免疫应答和适应性免疫应答的桥梁[6]。
综上所述，DC在宿主抵御病原体感染中扮演着重要的角色，同时，病原体也可通过多种途径调控DC的抗原提呈功能，从而逃避宿主免疫杀伤[7]。因此，本文就Mtb调控DC功能相关的研究进行总结梳理，旨在为后续相关研究提供理论参考。
1 树突状细胞
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DC存在于所有哺乳动物组织中，在适应性免疫反应的启动和调节以及先天免疫中起关键作用[8]。未成熟的DC存在于外周组织中，具有较强的迁移能力，通过其表达的受体识别病变细胞和病原体[9]；而成熟的DC主要存在于次级淋巴器官中，加工自身和非自身抗原并提呈给初始T淋巴细胞，处于启动、调控并维持免疫应答的中心环节[9]。
1.1 DC亚群与功能
由于DC在生理和病理条件下对于控制免疫反应具有重要作用，因此其亚群和发育起源得到了广泛的研究，并被认为是潜在的治疗靶点。DC起源于造血干细胞，广泛分布于血液、组织和淋巴器官中[10]。按照发育过程和所需转录因子，DC可分为传统树突状细胞(conventional DC, cDC)和浆细胞样树突状细胞(plasmacytoid DC, pDC)，其中cDC又分为传统I型树突状细胞(cDC1)和传统II型树突状细胞(cDC2)[11]。不同DC亚群的表面标记物及功能由相关转录因子调控(表1)。
在稳态条件下，cDC1在血液和组织中的出现频率约为cDC2的1/10[22]。cDC1广泛分布于血液、皮肤和淋巴器官中，是一种高效的交叉提呈细胞，在坏死细胞相关成分的交叉提呈方面具有较强能力[23]。在体外实验中，cDC1能促进细胞毒性CD8+ T细胞的分化[13]。
cDC2广泛存在于外周组织和淋巴器官中，尤其在T细胞与B细胞(T-B)的边界富集[22]。来自血液、淋巴器官、皮肤和肺的cDC2可诱导CD4+ T细胞在体外极化为辅助性T细胞1 (T helper cell 1, Th1)和Th2细胞[23-25]。在细胞因子分泌方面，cDC2除能高效产生白介素12 (IL-12p70)外，还可分泌白介素23 (IL-23)和激活素A[13,26]。
对于pDC的描述最早出现在20世纪50年代对人类淋巴结的研究中[27]。这些细胞能够分泌大量I型干扰素(type I interferon, IFN-I)，从而抵抗病原体[28-29]，而这一功能与pDC的分化密切相关[30]。pDC通过Toll样受体(Toll-like receptor, TLR) 7和TLR9识别病原体或自身核酸后，产生I型干扰素，在病毒防御中发挥关键作用[31-32]。
1.2 DC的抗原提呈机制
DC是机体调节免疫反应的关键细胞[9]。作为组织哨兵，DC不断从其局部环境中摄取、加工并通过主要组织相容性复合物(major histocompatibility complex, MHC)提呈抗原，诱导固有和适应性免疫细胞的激活，以清除病原体[33-34]。DC提呈抗原的方式主要包括蛋白酶体途径和溶酶体途径，此外，DC还可以通过交叉提呈的方式提呈抗原，虽然这不是主要方式，但能更广泛地激活T细胞，有利于机体免疫应答(图1)。
1.2.1 内源性抗原的提呈——蛋白酶体途径
对于内源性抗原，如胞内蛋白、核蛋白、病毒蛋白等，DC通过蛋白酶体将其降解为多肽，随后由抗原加工相关转运蛋白(transporter associated with antigen processing, TAP)将其转运至内质网，在内质网中与MHC-I分子结合，形成MHC-I-抗原肽复合物，提呈给细胞毒性T淋巴细胞(cytotoxic T-lymphocyte, CTL)[34]。该途径在激活抗肿瘤CD8+ T细胞反应中发挥重要作用[35]。
1.2.2 外源性抗原的提呈——溶酶体途径
MHC-Ⅰ类分子几乎在所有细胞表面表达，而MHC-Ⅱ类分子主要在免疫细胞上表达。抗原首先通过吞噬作用或受体介导的内吞作用被细胞捕获。DC通过其丰富的C型凝集素受体和Fc受体(Fc receptor, FcR)摄取外周组织环境中的抗原并将其内化，内化后大多数抗原被消化成肽段，通过肽-MHC-II与TCR的相互作用及共刺激信号传导，引发CD4+ T细胞的抗原特异性激活和扩增[36]。因此，在DC成熟过程中，MHC-II分子表达量会增加数倍，并伴随着其定位的变化：未成熟DC的MHC-II分子主要存在于内体中，而成熟DC的MHC-II分子主要位于质膜上[37]。
1.2.3 抗原交叉提呈
除了上述2种途径外，DC还可以通过交叉提呈的方式，利用MHC-I分子提呈细胞外环境中的抗原。外源抗原被吞噬入细胞后可从内体进入胞质，随后被蛋白酶体加工，并加载到内质网中的MHC-I类分子上[38-39]。
2 结核分枝杆菌调控树突状细胞抗原提呈的机制
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当Mtb通过呼吸道被摄入体内时，首先会面临DC等固有免疫细胞的防御，其表达的Toll样受体、Nod样受体和C型凝集素受体能够有效识别Mtb的多种成分，如脂蛋白LprG和磷脂酰肌醇甘露糖苷(phosphatidylinositol mannosides, PIMs)等，从而激活宿主细胞的自噬、炎性反应和凋亡等免疫防御信号通路[40] (图2)。在与宿主免疫系统的长期对抗中，Mtb进化出了多种保守策略以逃逸免疫杀伤，进而促进其生长和传播，例如抑制细胞抗菌肽的生成、阻碍吞噬体的成熟以及调控细胞自噬等，这些机制构成了感染相关研究中的一个复杂过程[41]。Mtb与宿主的相互作用结果是决定疾病是否发生的关键[42]。近年来，越来越多的研究表明，Mtb主要通过抑制抗原提呈细胞(antigen-presenting cells, APC)的吞噬作用、自噬过程、抑制DC的成熟以及调控APC的分化等多种策略操纵DC的抗原提呈功能[40,43-47]。
2.1 受体介导的识别与入侵
如前所述，DC表达一系列病原体识别受体(pattern recognition receptors, PRR)，包括TLR和C型凝集素受体，它们可以识别病原体表达的分子模式[48]。每个TLR可识别特定的抗原，例如脂蛋白、脂多糖(lipopolysaccharides, LPS)或细菌DNA[49]。LPS是革兰氏阴性细菌细胞壁的一个组成部分，可被TLR4识别，而肽聚糖(peptidoglycan, PGN)是另一种细菌细胞壁的成分，可刺激TLR2[50]。Su等[51]研究发现，Rv1016c脂蛋白是一种新型TLR2配体，在分枝杆菌感染过程中，Rv1016c一方面可诱导依赖于TLR2的细胞凋亡，另一方面也会通过依赖于TLR2和丝裂原活化蛋白激酶(mitogen-activated protein kinase, MAPK)信号通路的方式抑制MHC-II的表达和抗原加工，从而降低CD4+ T细胞的识别能力，从而允许细胞内分枝杆菌的持续存活。
2.2 Mtb对DC分化和成熟的调控
Balboa等[52]发现，经伽马射线处理的Mtb可影响单核细胞衍生的DC的分化，进而减少特异性T细胞的增殖，这与IL-10的分泌和TLR2的激活有关。尽管IL-10会抑制单核细胞分化为DC，但它会促进其成熟为巨噬细胞[53]。相比之下，巨噬细胞在抑制Mtb生长方面优于DC，这有助于机体清除Mtb[54]。
Mtb的某些蛋白可促进DC的成熟。例如，早期分泌性抗原6 (early secreted antigenic target of 6 kDa, ESAT-6)和复苏促进因子E (resuscitation-promoting factor E, RpfE)可通过TLR2和TLR4依赖的方式诱导DC的成熟，并促进Th1和Th17型T细胞免疫[55-56]。此外，Mtb通过TLR依赖的方式特异性结合树突状细胞特异性黏附分子-3-结合非整合素分子(dendritic cell-specific intercellular adhesion molecule-3-grabbing non-integrin, DC-SIGN)，诱导活性氧(reactive oxygen species, ROS)的产生，进而促进DC的成熟[57]。PPE60可通过MAPK和核因子激活的B细胞的κ-轻链增强(nuclear factor kappa-light-chain-enhancer of activated B cells, NF-κB)通路诱导DC成熟，增强DC的MHC-II表达和抗原加工[58]。Mtb的Rv1509蛋白通过增加CD80和MHC-II的表达，并与TLR2相互作用下调DC-SIGN的表达，从而促进DC成熟，诱导小鼠抗原特异性CD4+ T细胞和CD8+ T细胞数量的增加[59]。此外，HSP70、Rv0462、PstS1和Rv3812均被证明能够诱导DC成熟，并在引发针对Mtb的保护性免疫反应中发挥作用[60-63]。
然而，更多Mtb抗原通过抑制DC分化和成熟来逃避免疫反应。Mtb在潜伏感染期间上调其α晶状体蛋白1 (alpha-crystallin 1, Acr1)的表达，从而抑制DC的成熟[64]。Chen等[65]研究发现，Mtb蛋白复合物PE25/PPE41在体外可诱导小鼠骨髓来源的树突状细胞(bone marrow-derived dendritic cell, BMDC)成熟，增加共刺激分子CD80、CD86和MHC-II的表达，进而通过分泌促炎细胞因子IL-4和IL-10促进Th2极化。Mtb细胞壁成分脂阿拉伯甘露聚糖(mannose-capped lipoarabinomannan, ManLAM)与DC-SIGN结合破坏TLR信号通路[44]，导致IL-10的过度产生，进而抑制DC成熟[66]。Mtb丝氨酸水解酶1 (hydrolase important for pathogenesis 1, Hip1)可抑制促炎反应并损害DC功能，研究发现全长GroEL2蛋白具有诱导DC中促炎细胞因子产生的能力，并促进DC成熟和抗原提呈，但Hip1介导的GroEL2剪切体免疫刺激性差，无法促进DC成熟和抗原提呈[67]。Mtb的Rv1016c通过与TLR2、信号传导及转录激活蛋白(signal transducer and activator of transcription, STAT)和细胞因子信号抑制物3 (suppressor of cytokine signaling 3, SOCS3)通路相互作用抑制DC分化，从而损害初始T淋巴细胞向Th1和Th17细胞的分化[44,68]。此外，研究发现，Mtb在活动性结核病患者中大量释放MPT64蛋白，能够将未成熟的DC转化为髓系抑制性细胞(myeloid-derived suppressor cells, MDSC)，进而促进调节性T细胞(regulatory T cells, Treg)的产生，抑制Th1细胞和Th17细胞的分化，从而促进Mtb的存活[69]。
2.3 Mtb抑制吞噬体的酸化、成熟及其与溶酶体的融合
DC通过吞噬作用将Mtb内化后，吞噬体逐步酸化、成熟，并与溶酶体融合，发育为吞噬溶酶体，从而降解病原体。随后，DC将抗原提呈给T细胞，启动适应性免疫反应[70]。然而，Mtb已进化出多种策略抑制这一过程，以实现胞内存活[71]。Mtb的蛋白激酶G (protein kinase G, PknG)通过降低甘油激酶(glycerol kinase, GlpK)的表达，增强Ag85A和Ag85C的表达，从而抑制溶酶体的成熟[72]；此外，PknG还可通过增强宿主细胞内的信号转导来抑制吞噬体与溶酶体的融合[43,70]。蛋白酪氨酸磷酸酶A (protein tyrosine phosphatase, PtpA)可与液泡ATP酶(vacuolar ATPases, V-ATPases)的亚基H相互作用，阻止V-ATPases在吞噬体膜上打孔，进而抑制吞噬体的酸化[70,73]。Portal-Celhay等[74]的研究发现，Mtb通过分泌EsxH抑制宿主细胞的内体分选复合物(endosomal sorting complex required for transport, ESCRT)，而ESCRT是抗原加工所必需的；细胞实验表明，敲除EsxH后，Mtb激活的ESCRT依赖性T细胞增加，表明EsxH可通过抑制DC加工抗原的能力来阻碍CD4+ T细胞的激活和抗原提呈。近些年，关于Mtb的主要毒力因子磷酸二甲酯(phthiocerol dimycocerosates, PDIM)的研究较为热门，主要因为PDIM可在Mtb感染的多种细胞中发挥作用。Augenstreich等[75]研究表明，Mtb通过差异区域1 (region of difference 1, RD1)编码的ESX-1和PDIM协同作用诱导受感染巨噬细胞的吞噬体膜损伤和破裂。PDIM还可导致人淋巴内皮细胞中的溶酶体破裂，最终引发宿主细胞凋亡[76]。然而这种机制是否存在于DC中仍有待研究。
2.4 Mtb抑制自噬
Feng等[77]研究通过高剂量Mtb感染自噬缺陷型小鼠，首次发现CD11c+细胞的自噬受损时，会导致MDSC的过度积累。这些过度积累的MDSC携带大量细菌，进而导致抗原呈递细胞数量减少和肺部T细胞增殖降低，从而阻碍了持续的T细胞反应并破坏了对Mtb感染的控制。此外，Mittal等[78]研究揭示PDIM可保护Mtb免受LC3相关吞噬作用和经典自噬的影响。Hu等[79]研究发现，Mtb蛋白SapM可靶向宿主Rab7，从而抑制自噬体-溶酶体融合。2016年，一项研究通过对Mtb感染DC后抑制其MHC-II类限制性抗原提呈的基因位点进行全基因组筛选，鉴定出PE_PGRS47是Mtb的一种重要毒力因子[80]。进一步研究发现，编码PE_PGRS47蛋白的基因Rv2741发生靶向突变后，Mtb在体外和体内的生长速度减慢，同时PE_PGRS47突变体在感染小鼠后显著增强了DC的MHC-II类限制性抗原提呈，表明PE_PGRS47蛋白可抑制DC的抗原提呈功能，且与抑制受感染宿主吞噬细胞的自噬有关[80]。此外，通过Mtb感染的DC转录组基因分析发现与自噬相关的基因显著上调，进而发现Mtb可通过操纵宿主细胞microRNA-155的表达来调节Atg3，从而实现胞内存活[81]。Mtb的毒力因子Rv3416和Rv2463也可抑制DC的自噬，以建立长期感染[82-83]。本研究组在前期研究中发现，牛分枝杆菌可通过“劫持”巨噬细胞的线粒体自噬来抑制异源自噬，从而有利于其胞内存活[84]。DC中是否存在类似的机制仍有待进一步研究。
2.5 Mtb抑制抗原提呈相关分子的表达
Satchidanandam等[85]研究发现，通过卡介苗(Bacillus Calmette-Guérin, BCG)过表达Mtb的甘露糖基化蛋白Rv1860，可显著下调共刺激分子MHC-II、CD40、CD54、CD80和CD86的分泌，从而抑制DC的抗原提呈及其对T细胞的激活。Dolasia等[86]2021年的研究发现，Mtb的PPE18蛋白可抑制小鼠MHC II类抗原提呈；通过巨噬细胞与T细胞共培养实验发现，PPE18以剂量依赖性方式抑制巨噬细胞MHC-II类介导的抗原提呈，导致CD4+ T细胞活化较差；因此，Mtb可能利用PPE18来抑制MHC-II类抗原提呈，从而削弱适应性免疫反应的激活。DC中是否存在类似的机制仍有待进一步研究。
2.6 Mtb调控抗原提呈的其他机制
Srivastava等[87]研究发现，当Mtb入侵宿主后，若宿主固有免疫无法将其清除，招募到肺脏的DC也会被Mtb感染，进一步受感染的DC将Mtb运输到局部淋巴结，但激活CD4+ T细胞的效果不佳，主要是因为Mtb为了提高胞内存活的概率，通过抗原输出途径减少了抗原提呈，虽然抗原输出后其他细胞仍可提呈，但这并不能补偿受感染细胞抗原提呈的减少。这代表了细菌逃避抗原提呈的另一种策略。
综上所述，Mtb通过抑制自噬过程、吞噬作用、抑制DC的成熟以及抑制APC的分化等多种策略调控DC的抗原提呈过程(图3)。然而，Mtb是否存在某种成分能够抑制DC对包裹其成分的囊泡的降解或能够阻止DC表达MHC分子等机制尚不清楚。因此，研究Mtb操纵DC抗原提呈的分子机制具有重要的科学意义，可拓展和加深人类对Mtb免疫逃逸机制的认识，为结核病防控新策略的研发提供新的思路和理论依据。
3 基于促进抗原提呈的结核病新疫苗研制策略
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目前唯一注册用于控制人类结核病的疫苗是BCG，其免疫保护力只能维持10-15年[88]。Mtb的复杂性及其免疫保护标志物的不确定性阻碍了结核病疫苗的开发。作为胞内菌，Mtb入侵机体后主要引起细胞免疫反应，DC通过抗原提呈激活T细胞免疫反应[89]。因此，研究Mtb调控DC抗原提呈的机制可为新疫苗的开发提供靶标。
近年来，Mtb亚单位疫苗、重组BCG和减毒活疫苗的研究进展迅速[90]，主要通过不同组合的抗原提呈系统和亚单位疫苗，激活T细胞免疫反应以持续抵抗Mtb感染。研究表明，ESAT-6可激活受体，促进抗原提呈细胞的成熟[91]，并且能以TLR2和MyD88依赖性方式在DC中诱导IL-6和TGF-β，从而指导Th17细胞分化[92]。基于此，Kirk等[93]制备了ESAT-6/EsxA与Ag85B和EsxH的组合疫苗，结果表明，这种疫苗可增强长期记忆免疫应答。VPM1002是一种重组BCG，可分泌李斯特菌溶血素O，增加单核细胞增生李斯特菌的吞噬体逃逸[94]。通过敲除抑制吞噬体-溶酶体融合的脲酶C (urease C, ureC)，该疫苗能够增强李斯特菌溶血素O的活性，诱导吞噬细胞凋亡，使DC能够通过摄取凋亡囊泡有效地提呈抗原[94]。MTBVAC是一种减毒活疫苗，通过突变毒力基因phoP和fadD26抑制了DIM和海藻糖衍生脂质的合成[95]。与BCG相比，MTBVAC更能提高CD4+ T细胞的Th1和Th17活性，这可能是由于DC抗原提呈水平的提高有助于机体对病原体的清除[96]。
4 总结与展望
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尽管在过去几十年中人类对结核病的研究已经取得了巨大进展，但随着抗生素耐药性的增加[97]，要实现世界卫生组织设定的2035年终结结核病的目标，只能通过重大防控技术突破来实现，例如新型结核病疫苗的研制成功并得以广泛应用。然而，结核病防控技术的有效突破需要以深入理解Mtb-DC互作机制为基础。如前所述，大量研究表明Mtb在感染后抑制DC的成熟，选择合适的能够提高DC抗原提呈水平的抗原或TLR激动剂以激发更强的特异性免疫应答可能是有效的策略之一。因此，深入阐明Mtb如何调控DC的抗原处理与提呈过程是未来一个非常重要的研究方向。阐明Mtb-DC的互作机制，不仅可拓展对Mtb致病机制的认识，也有助于为新型长效结核病疫苗的研制提供理论基础和科学依据。
基金
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  • 国家重点研发计划(2023YFD1800700)
  • 甘肃省自然科学基金(22JR5RA712)
  • 甘肃省科技重大专项(22ZD6NA001)
  • 中国农业科学院创新工程项目(CAAS-ASTIP-2021-LVRI)
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2025年第65卷第5期
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doi: 10.13343/j.cnki.wsxb.20240678
  • 接收时间：2024-11-02
  • 首发时间：2026-02-05
  • 出版时间：2025-05-04
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  • 收稿日期：2024-11-02
  • 录用日期：2025-02-09
基金
National Key Research and Development Program of China(2023YFD1800700)
国家重点研发计划(2023YFD1800700)
Natural Science Foundation of Gansu Province(22JR5RA712)
甘肃省自然科学基金(22JR5RA712)
Science and Technology Major Project of Gansu Province(22ZD6NA001)
甘肃省科技重大专项(22ZD6NA001)
Innovation Program of Chinese Academy of Agricultural Sciences(CAAS-ASTIP-2021-LVRI)
中国农业科学院创新工程项目(CAAS-ASTIP-2021-LVRI)
作者信息
    1.中国农业科学院兰州兽医研究所/兰州大学 动物医学与生物安全学院，动物疫病防控全国重点实验室 甘肃 兰州
    2.甘肃省疾病预防控制中心 甘肃 兰州
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https://castjournals.cast.org.cn/joweb/wswxb/CN/10.13343/j.cnki.wsxb.20240678
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2种不同金属材料的力学参数
科
Family		 属数
Number of
genus		 种数
Number of
species		 占总种数比例
Percentage of
total species (%)		 属
Genus		 种数
Number of
species		 占总种数比例
Percentage of total
species (%)
鹅膏菌科Amanitaceae 2 11 5.26 鹅膏菌属 Amanita 10 4.78
小菇科 Mycenaceae 2 12 5.74 丝盖伞属 Inocybe 5 2.39
多孔菌科 Polyporaceae 8 14 6.70 蜡蘑属 Laccaria 5 2.39
红菇科 Russulaceae 3 23 11.00 小皮伞属 Marasmius 6 2.87
小菇属 Mycena 11 5.26
光柄菇属 Pluteus 5 2.39
红菇属 Russula 17 8.13
栓菌属 Trametes 5 2.39
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