γδT细胞在幽门螺杆菌感染中的作用特点及机制研究
摘要
幽门螺杆菌(Helicobacter pylori, H. pylori)是一种微需氧、螺旋状革兰阴性杆菌，主要感染定植于人体胃粘膜。流行病学调查显示，全球50%以上人口都曾感染过H.pylori，其感染可导致慢性胃炎，继而引起消化性溃疡和粘膜相关淋巴样组织淋巴瘤(MALT)，甚至与胃腺癌的发生发展密切相关，已被WHO列为Ⅰ类致癌因子。尽管H. pylori感染能够引发宿主较强烈的固有免疫和获得性免疫应答，但自然感染H. pylori后机体的免疫反应并不能有效清除细菌，反而由于慢性持续性感染导致胃粘膜免疫病理损害。目前，H. pylori慢性持续性感染机制及相关的免疫调控机制并不完全清楚。
T淋巴细胞免疫在H. pylori感染所致疾病的发展进程具有重要的作用。根据TCR双肽链构成的不同，可将T细胞分为β T细胞和γ T细胞两类。 β T细胞作为重要的效应细胞在获得性免疫应答中发挥主要作用，而γ T细胞由于其分布特点和抗原识别特性，在机体的固有性免疫中发挥着独特的作用。γ T细胞主要分布于肠道、呼吸道皮肤及泌尿生殖道的黏膜和皮下组织，而脾脏和淋巴结中分布较少，外周血中γ T细胞仅占T淋巴细胞的2%～5%。粘膜组织是病原微生物入侵机体的第一道屏障，机体T细胞总库存的一半都在粘膜组织内。因此，γ T细胞这一分布特点提示其在细菌，病毒，真菌和原虫等病原体感染的黏膜免疫防御中都扮演着重要的角色。
γ T细胞在胃肠道粘膜大量存在，而胃粘膜正是H. pylori感染定植的主要部位，是细菌入侵的第一道免疫防线。因此，γ T细胞与H. pylori感染的关系日益受到重视，其免疫应答状况极可能决定了H. pylori的感染定植及相关疾病的转归。已有研究报道，H. pylori感染患者外周血中的γ T细胞明显增高，并且与胃炎严重程度密切相关，清除细菌后，γ T细胞数量亦相应减少。然而，γ T细胞在H. pylori感染中的应答规律;对细菌感染定植的具体作用;对H. pylori感染诱导的免疫应答的调节机制等，目前还不清楚。明确这些问题将有助于我们对H. pylori感染过程中免疫应答网络的全面理解和阐述，为采取正确的免疫调控方式逆转其慢性持续化进程提供新的线索。
【研究目的】
1.本研究以γ T细胞为主要研究对象，探讨其在H. pylori感染过程中的应答规律及特点。
2.分析γ T细胞对H. pylori定植量和炎症程度的影响。明确其在H. pylori感染中的作用。
3.探讨γ T细胞影响H. pylori感染定植的免疫调节机制
4.初步分析H. pylori感染患者外周血γ T细胞特点
【研究方法】
1．H．pylori感染过程中γ T细胞的应答特征
建立H. pylori感染C57BL/6小鼠模型，在H. pylori感染后不同时间点处死小鼠，分离小鼠的脾，Peyer's结，肠系膜淋巴结及小肠上皮间淋巴细胞，采用流式细胞技术，分析γ T细胞的应答规律及表型特征。细胞内因子染色，检测γ T细胞分泌细胞因子谱。同时，利用IL-23p19~(-/-)敲除小鼠研究IL-23对IL-17~+γ T细胞的调节作用。
2．γ T细胞在H. pylori感染中的作用研究
H. pylori感染野生型小鼠及γ T细胞基因敲除小鼠，采用real-time PCR检测H.pylori定植量的变化，H&E染色检测胃组织炎症程度。随后，体外扩增分选感染小鼠脾脏中的γ T细胞。在H. pylori感染前24小时，通过静脉过继免疫TCR--/-小鼠，检测其对细菌定植量及胃组织炎症的影响。
3. γ T细胞在H. pylori感染中的作用机制探讨
H. pylori感染野生型小鼠及γ T细胞基因敲除小鼠，采用流式细胞技术，分析γT细胞缺失后机体Th细胞免疫应答变化；抽提感染胃组织RNA，real-time PCR检测细胞因子、趋化因子和基质金属蛋白酶(MMPs)变化，ELISA检测感染小鼠血清及胃粘膜局部IgG和IgA抗体水平。
4. H. pylori感染患者外周血中γ T细胞分析
收集新桥医院消化内科H. pylori阳性(25例)和H. pylori阴性(18例)胃炎患者的外周血标本。采用流式细胞技术，分析γ T细胞比例变化及细胞亚群应答情况。
【研究结果】
1. γ T细胞在H. pylori感染过程中的应答特征
1.1感染H. pylori后，小鼠系统及局部免疫系统中γ T细胞应答明显增强，小鼠脾及肠系膜淋巴结中的γ T细胞的比例在感染H. pylori24h后即开始明显升高(P <0.05)，48h达到高峰。而PP结及肠上皮间淋巴细胞中γ T细胞于感染后24h即达到峰值，并且在感染早期(7d)都维持在较高水平。
1.2体外以H. pylori感染小鼠脾脏CD3~+T淋巴细胞。结果显示，H. pylori活菌可明显诱导γ T细胞扩增(P <0.05)，而甲醛固定菌株则不能诱导增殖。并且H. pylori这种诱导扩增活性与H. pylori毒力蛋白CagA和UreB无关。
1.3分析γ T细胞表型特点发现，H. pylori感染后，脾脏中γ T细胞表现为激活状态，CD44，CD69和CD25的表达上调。
1.4采用流式细胞技术检测应答γ T细胞的不同亚型，尽管Vγ1~+γ T细胞是脾淋巴细胞中主要的γ T细胞亚型，但H. pylori感染小鼠的脾淋巴细胞中主要以Vγ4~+γ T细胞应答为主，其比例明显升高。而相应的Vγ1~+γ T细胞所占比例降低(P <0.05)。采用real-time PCR检测胃粘膜局部γ T细胞的Vγ亚型，结果表明小鼠胃粘膜主要以Vγ7~+γ T细胞为主。H. pylori感染后Vγ7水平略微升高，同时Vγ4~+γ T细胞在胃粘膜聚集，可检测到明显的Vγ4基因表达。
1.5采用流式细胞技术检测H. pylori感染小鼠应答γ T细胞的细胞因子谱，结果表明，γ T细胞分泌IL-4，IL-10及IL-22的水平较低，主要以分泌IL-17和IFN-γ为主，其中感染后IL-17~+γ T细胞的比例明显升高，48小时达到顶峰，且一直维持较高水平(P <0.01)。而IFN-γ~+γ T细胞感染前后无显著变化。并且，IL-17~+γ T细胞是H. pylori感染早期主要的IL-17来源。结果提示，γ T细胞可能通过分泌IL-17参与了H. pylori感染的免疫应答。
1.6H. pylori感染过程中γ T细胞分泌IL-17依赖于IL-23的表达。
2. γ T细胞在H. pylori感染中的具体作用
2.1H. pylori分别感染野生型及γ T细胞敲除小鼠，结果显示敲除小鼠胃粘膜H.pylori定植量及组织炎症程度均显著高于野生型小鼠(P <0.05)。提示γ T细胞在H.pylori可能发挥免疫保护性作用。
2.2我们采用体外扩增的γ T细胞过继免疫TCR--/-小鼠后再感染H. pylori，检测细菌定植量和胃组织炎症的变化。与HBSS处理组相比，过继免疫组H. pylori感染后胃粘膜H. pylori定植量及组织炎症程度均显著降低(P <0.05)。结果进一步证实了γT细胞在抵御H. pylori感染定植中的保护性作用。
3. γ T细胞在H. pylori感染中的作用机制研究
3.1采用流式细胞技术分析了H. pylori感染后野生型小鼠与敲除小鼠的适应性免疫应答(Th细胞)的变化。结果显示，敲除γ T细胞后，Th17和Th22细胞的特异性免疫应答增强，而Th1和Th2型细胞免疫应答则减弱。胃粘膜组织real-time PCR结果也显示，敲除小鼠感染H. pylori后，IL-17水平在感染早期较野生型小鼠低，而在感染后期(28d)，其水平则显著升高。感染后期的IFN_(-γ)表达则明显减弱。提示，γ T细胞可能通过影响后续的适应性免疫应答参与了H. pylori感染的免疫保护效应。
3.2感染早期γ T细胞敲除小鼠胃粘膜中性粒细胞趋化相关的细胞因子及趋化因子(CXCL1, CXCL2, IL-6, GM-CSF, TNF-)水平降低。提示γ T细胞可能通过分泌IL-17诱导中性粒细胞的募集控制H. pylori早期感染的增殖扩散。
3.3分析了H. pylori感染后野生型小鼠与敲除小鼠血清及胃粘膜的IgG和IgA抗体水平。结果显示，γ T细胞敲除后，血清IgG水平无明显改变(P>0.05)，而粘膜局部的IgA水平则明显减低(P <0.05)。说明γ T细胞在粘膜局部抗体的产生过程中发挥一定作用。
3.4γ T细胞缺失后，感染小鼠胃组织中趋化因子CCL2，CCL25及CXCL1的表达与野生型小鼠相比显著升高(P <0.05)，而CCL28的表达则明显减低(P <0.05)。其他趋化因子CCL5，CCL20和CXCL2表达并无明显改变(P>0.05)。
3.5敲除γ T细胞后， H. pylori感染小鼠胃组织MMP-9的表达显著升高,MMP-7的表达则明显减低(P <0.05)，其他MMP-2，MMP-3和MMP-13的表达没有显著变化。
以上结果提示我们γ T细胞可能通过影响部分MMP及趋化因子的表达参与H.pylori感染后的免疫调控及炎症反应。
4. H. pylori感染患者外周血中γ T细胞分析
γ T细胞在H. pylori感染和未感染患者外周血中的比例并无明显变化(P>0.05)。然而，相对于H. pylori阴性患者，H. pylori感染患者外周血中产IL-17和IL-22的γ T细胞比例明显升高(P <0.05)。并且外周血中存在IFN-γ，IL-17~+或IL-22~+共表达的γ T细胞。
【主要结论】
1. H. pylori感染后可以迅速激活诱导γ T细胞应答。PP结及iIEL是H. pylori感染后较早应答的免疫场所。应答的γ T细胞主要是Vγ4亚型，并且以分泌IL-17的γT细胞为主，这类IL-17~+γ T细胞主要依赖于IL-23的表达。
2. γ T细胞在H. pylori感染中主要发挥免疫保护性作用。
3.早期应答的γ T细胞可能通过影响H. pylori特异的适应性免疫应答(细胞免疫和体液免疫)，调节部分MMP以及趋化因子的表达参与了H. pylori的定植量及炎性反应强度的控制。
4. H. pylori感染患者外周血γ T细胞比例无显著变化，但IL-17~+γ T细胞明显升高，提示γ T细胞可能通过分泌IL-17参与了机体的免疫应答。
【研究意义】
H. pylori感染的免疫机制研究以前主要集中在慢性持续性感染诱导的适应性免疫应答反应，而感染初期的固有免疫系统的作用并不完全清楚。γ T细胞作为连接固有免疫和适应性免疫系统的重要桥梁，在感染性疾病中发挥重要作用。深入了解这群细胞在H. pylori感染中的作用及免疫调控机制有助于全面阐述H. pylori感染慢性持续化致病机制，为采取正确的免疫调控方式逆转其慢性持续化进程提供新的线索。
Helicobacter pylori (H. pylori) are a Gram-negative, microaerophilic bacterium thatspecifically resides in the surface mucous layer of gastric mucosa. Epidemiological datademonstrate that there are more than50%of the population worldwide infected with H.pylori, which may cause chronic active gastritis, leading to peptic ulcer disease,mucosa-associated lymphoid tissue lymphoma and gastric adenocarcinoma. Although H.pylori infection elicits specific humoral and cellular immune responses, the bacteriumpersists and the inflammation continues for decades.
T lymphocyte plays a critical role in the pathogenesis of persistent H. pylori infection.Traditionally, two subsets of T cells have been defined: β T cells and γ T cells. To date,studies of immune responses to H. pylori have largely focused on β~+CD4~+T helper cells.However, innate immune response of γ T cells to H. pylori infection has yet to beelucidated. γ T cells are a minor T cell subset present in the spleen and lymph nodes, butrepresent a major subset within the epithelia of intestine and skin. γ T cells play animportant role in the recognition of unrestricted major histocompatibility complex (MHC)molecules and contribute to mucosal defense against invading pathogens.
H pylori have a particular tropism for the gastric epithelium, and γ T cells are mainlylocalized in mucosal tissues and abundant in the gastrointestinal tract. Thus, the relationshipbetween development and differentiation of γ T cells and the progression of H. pyloriinfection raise great concerns. Previous study reported that the percentage of γ T cellssignificantly increased in the H. pylori positive group in comparison with healthy controls.After H. pylori eradication therapy, the γ T cell count significantly decreased. However,the characteristics and role of γ T cell response in H. pylori infection have not beenelucidated. In addition, the detailed mechanism through which γ T cell regulates andaffects the system immune response is not clear.
【Objectives】
1. Try to characterize γ T cell responses to H. pylori shortly after infection of a C57BL/6mouse model.
2. Aim to elucidate the role of γ T cells in the early phase of H. pylori infection
3. To explore the mechanism through which γ T cell regulates and affects the immuneresponse to H. pylori infection
4. To analyze human peripheral blood γ T cells response in H. pylori-infected patients
【Methods】
1. C57BL/6mice were orogastrically challenged with H. pylori and lymphocytes ofspleen, Peyer's patches(PP), mesenteric lymph node(MLN) and intestinal intraepitheliallymphocytes(iIEL) were collected at the indicated times post-infection. γ T cells responseswere examined to analyze the characteristics, subsets and cytokine profiles by flowcytometry.
2. Wild-type (WT) C57BL/6and γ T cell-deficient (TCR--/-) mice was infected withH. pylori orally. The bacteria load in gastric tissue was measured with real-time PCR todetect the16s rDNA of H. pylori and the gastric inflammation was evaluated by H&Estaining. In addition, γ T cells were expanded from splenocytes in vitro and were i.v.transferred into TCR--/-mice before H. pylori infection to assay the effects of γ T cells onthe colonization and inflammation.
3. Wild-type (WT) C57BL/6and γ T cell-deficient (TCR--/-) mice was infected withH. pylori orally. Splenic lymphocytes were collected for analysis of specific Th1, Th2,Th17and Th22response by intracellular staining. Moreover, cytokines, chemokines andMMPs mRNA expression was detected by real-time PCR. Serum IgG and mucosal IgAwere evaluated by ELISA.
4. The peripheral blood mononuclear cells were isolated from25H. pylori-positivepatients with chronic antral gastritis and18H. pylori-negative healthy controls. To detectand analyze CD3, TCR γ, IFN-γ, IL-17and IL-22using flow cytometry.
【Results】
1. The characteristics of γ T cell response to H. pylori infection
1.1Following H. pylori challenge, the proportion of γ T cell in the lymphocytes ofspleen, Peyer's patches, mesenteric lymph node and intraepithelial lymphocytes wassignificantly increased. In the spleen and MLN, γ T cell was expanded from24h pi and reach a peak at48h pi, whereas in the PP and iIEL γ T cell reach its peak at24h pi. Thetime course of γ T cell responses in different organs suggests that PP and iIEL may be twoearlier sites of γ T cell priming during H. pylori infection.
1.2Purified spleen CD3~+T cells were co-cultured with viable H. pylori or fixedbacteria. Only viable H. pylori induce the expansion of γ T cell (P <0.05). The lack ofCagA or UreB could not show the obvious influences on γ T cell proliferation (P>0.05).
1.3Following H. pylori challenge, γ T cell exhibit increased CD69, CD44and CD25expression (P <0.05).
1.4Analysis of the γ T cell subsets in the spleen demonstrated that Vγ4~+cells seemedto be responsible for the rapid increase in the population of γ T cell (P <0.05). In thegastric mucosa, Vγ7were the dominant γ T cell population. After H. pylori infection, theexpression of the Vγ4gene increased.
1.5Effect of H. pylori infection on cytokine profiles of γ T cells was investigated,IL-4-, IL-10-and IL-22-producing γ T cells comprise a very small part of γ T cells and nosignificant change was observed after H. pylori infection. IFN-γ-and IL-17-producing γ Tcells were the dominant population. IFN-γ~+γ T cells did not change significantly (P>0.05),whereas the percentage of IL-17~+γ T cells significantly was increased at24h pi and reacha peak at48h, even persisted for the follow-up time points(P <0.01). At the early stage ofH. pylori infection, IL-17~+γ T cells were the major source of IL-17. In addition,IL-23-mediated signaling induced IL-17production by γ T cells.
2. The protective role of γ T cells in H. pylori infection.
2.1The colonization of H. pylori and the inflammation of gastric mucosa in the γ Tcell-deficient were significantly higher than that in the WT mice (P <0.05), suggesting thatdeletion of γ T cells might impair host defense against H. pylori infection.
2.2γ T-cell-transferred mice showed significantly lower copies of H. pylori thanthose from HBSS-treated mice (P <0.05). In addition, the mean microscopical score of γT-cell-transferred mice were significantly lower compared to HBSS-treated mice (P <0.05). These results indicate that γ T cells might increase the resistance to H. pyloriinfection.
3. The effect of γ T cells on host immune response to H. pylori infection
3.1Splenic lymphocytes from TCR--/-mice showed significantly higher Th17and Th22cell responses than those from WT mice when stimulated with H. pylori whole cellprotein or PMA/ionomycin. On the contrary, Th1and Th2cell responses were significantlyattenuated. In addition, at the early stage of infection, expression of IL-17mRNA waslower in gastric mucosa from TCR--/-mice than those of from WT mice, whereas at28d piIL-17mRNA was expressed at a higher level. IFN_(-γ)mRNA was expressed at a lower levelin the gastric mucosa of TCR--/-mice than those in WT mice. These results suggest thatlack of γ T cells might have an effect on specific Th cell responses to H. pylori infection.
3.2Decreased expression of neutrophil-inducing cytokine/chemokine in the stomachof infected TCR--/-mice
3.3Deletion of γ T cell led to attenuated production of gastric mucosal H. pylorispecific IgA (P <0.05), but it had no significant effect on the level of serum IgG (P>0.05).
3.4H. pylori infected TCR--/-mice showed significantly increase of CCL2, CXCL1and CCL25mRNA expression compared with those of infected WT mice (P <0.05).Whereas, CCL28mRNA was expressed at a lower level in comparison with that of infectedWT mice (P <0.05). Other detected chemokines, such as CCL5, CCL20and CXCL2wasnot significantly changed.
3.5Lack of γ T cells led to increased expression of MMP-9mRNA and reducedexpression of MMP-7(P <0.05). No significant change of other MMPs (MMP-2, MMP-3and MMP-13) was observed. These results imply that γ T cells may exert its effect on theH. pylori infection by enhancing or attenuating expression of chemokines and MMPs.
4. The frequency of γ T cells in H. pylori-positive patients was not significantlydifferent compared to those of healthy controls (P>0.05). However, we observed thatIL-17-producing γ T cells were one important source of IL-17in response to H. pyloriinfection. Moreover, the subsets of IL-17-and IL-22-producing, not IFN-γ-producing γ Tcells markedly increased (P <0.05).
【Conclusion】
1. H. pylori infection induced rapidly γ T cells response in the C57BL/6mousemodel. The γ T cells responses occurred earlier in the PP and iIEL than in the spleen orMLN. Vγ4~+γ T cells were responsible for the increased population of γ T cell. Moreover,IL-17produced by γ T cells was the dominant source of IL-17at the early stage of H.pylori infection. IL-23-mediated signaling induced IL-17production by γ T cells.
2. γ T cells play a protective role in H. pylori infection.
3. The role of γ T cells on H. pylori infection might be associated with alteredspecific adaptive immune response and the expression of cytokines/chemokines and MMPs.
4. γ T cells might involve human immune response to H. pylori infection via production ofIL-17.
【significance】
Previous studies largely focused on the adaptive immune response to H. pyloriinfection. Innate immune response to H. pylori infection has yet to elucidate. As a bridgebetween the innate and the adaptive immune system, γ T cells played an indispensible rolein pathogen elimination and immune regulation. A better understanding of thecharacteristics, function and regulation of γ T cells responses to H. pylori infection mayhelp us to explore novel and effective immunotherapies for gastric diseases induced by thisorganism.
T淋巴细胞免疫在H. pylori感染所致疾病的发展进程具有重要的作用。根据TCR双肽链构成的不同，可将T细胞分为β T细胞和γ T细胞两类。 β T细胞作为重要的效应细胞在获得性免疫应答中发挥主要作用，而γ T细胞由于其分布特点和抗原识别特性，在机体的固有性免疫中发挥着独特的作用。γ T细胞主要分布于肠道、呼吸道皮肤及泌尿生殖道的黏膜和皮下组织，而脾脏和淋巴结中分布较少，外周血中γ T细胞仅占T淋巴细胞的2%～5%。粘膜组织是病原微生物入侵机体的第一道屏障，机体T细胞总库存的一半都在粘膜组织内。因此，γ T细胞这一分布特点提示其在细菌，病毒，真菌和原虫等病原体感染的黏膜免疫防御中都扮演着重要的角色。
γ T细胞在胃肠道粘膜大量存在，而胃粘膜正是H. pylori感染定植的主要部位，是细菌入侵的第一道免疫防线。因此，γ T细胞与H. pylori感染的关系日益受到重视，其免疫应答状况极可能决定了H. pylori的感染定植及相关疾病的转归。已有研究报道，H. pylori感染患者外周血中的γ T细胞明显增高，并且与胃炎严重程度密切相关，清除细菌后，γ T细胞数量亦相应减少。然而，γ T细胞在H. pylori感染中的应答规律;对细菌感染定植的具体作用;对H. pylori感染诱导的免疫应答的调节机制等，目前还不清楚。明确这些问题将有助于我们对H. pylori感染过程中免疫应答网络的全面理解和阐述，为采取正确的免疫调控方式逆转其慢性持续化进程提供新的线索。
【研究目的】
1.本研究以γ T细胞为主要研究对象，探讨其在H. pylori感染过程中的应答规律及特点。
2.分析γ T细胞对H. pylori定植量和炎症程度的影响。明确其在H. pylori感染中的作用。
3.探讨γ T细胞影响H. pylori感染定植的免疫调节机制
4.初步分析H. pylori感染患者外周血γ T细胞特点
【研究方法】
1．H．pylori感染过程中γ T细胞的应答特征
建立H. pylori感染C57BL/6小鼠模型，在H. pylori感染后不同时间点处死小鼠，分离小鼠的脾，Peyer's结，肠系膜淋巴结及小肠上皮间淋巴细胞，采用流式细胞技术，分析γ T细胞的应答规律及表型特征。细胞内因子染色，检测γ T细胞分泌细胞因子谱。同时，利用IL-23p19~(-/-)敲除小鼠研究IL-23对IL-17~+γ T细胞的调节作用。
2．γ T细胞在H. pylori感染中的作用研究
H. pylori感染野生型小鼠及γ T细胞基因敲除小鼠，采用real-time PCR检测H.pylori定植量的变化，H&E染色检测胃组织炎症程度。随后，体外扩增分选感染小鼠脾脏中的γ T细胞。在H. pylori感染前24小时，通过静脉过继免疫TCR--/-小鼠，检测其对细菌定植量及胃组织炎症的影响。
3. γ T细胞在H. pylori感染中的作用机制探讨
H. pylori感染野生型小鼠及γ T细胞基因敲除小鼠，采用流式细胞技术，分析γT细胞缺失后机体Th细胞免疫应答变化；抽提感染胃组织RNA，real-time PCR检测细胞因子、趋化因子和基质金属蛋白酶(MMPs)变化，ELISA检测感染小鼠血清及胃粘膜局部IgG和IgA抗体水平。
4. H. pylori感染患者外周血中γ T细胞分析
收集新桥医院消化内科H. pylori阳性(25例)和H. pylori阴性(18例)胃炎患者的外周血标本。采用流式细胞技术，分析γ T细胞比例变化及细胞亚群应答情况。
【研究结果】
1. γ T细胞在H. pylori感染过程中的应答特征
1.1感染H. pylori后，小鼠系统及局部免疫系统中γ T细胞应答明显增强，小鼠脾及肠系膜淋巴结中的γ T细胞的比例在感染H. pylori24h后即开始明显升高(P <0.05)，48h达到高峰。而PP结及肠上皮间淋巴细胞中γ T细胞于感染后24h即达到峰值，并且在感染早期(7d)都维持在较高水平。
1.2体外以H. pylori感染小鼠脾脏CD3~+T淋巴细胞。结果显示，H. pylori活菌可明显诱导γ T细胞扩增(P <0.05)，而甲醛固定菌株则不能诱导增殖。并且H. pylori这种诱导扩增活性与H. pylori毒力蛋白CagA和UreB无关。
1.3分析γ T细胞表型特点发现，H. pylori感染后，脾脏中γ T细胞表现为激活状态，CD44，CD69和CD25的表达上调。
1.4采用流式细胞技术检测应答γ T细胞的不同亚型，尽管Vγ1~+γ T细胞是脾淋巴细胞中主要的γ T细胞亚型，但H. pylori感染小鼠的脾淋巴细胞中主要以Vγ4~+γ T细胞应答为主，其比例明显升高。而相应的Vγ1~+γ T细胞所占比例降低(P <0.05)。采用real-time PCR检测胃粘膜局部γ T细胞的Vγ亚型，结果表明小鼠胃粘膜主要以Vγ7~+γ T细胞为主。H. pylori感染后Vγ7水平略微升高，同时Vγ4~+γ T细胞在胃粘膜聚集，可检测到明显的Vγ4基因表达。
1.5采用流式细胞技术检测H. pylori感染小鼠应答γ T细胞的细胞因子谱，结果表明，γ T细胞分泌IL-4，IL-10及IL-22的水平较低，主要以分泌IL-17和IFN-γ为主，其中感染后IL-17~+γ T细胞的比例明显升高，48小时达到顶峰，且一直维持较高水平(P <0.01)。而IFN-γ~+γ T细胞感染前后无显著变化。并且，IL-17~+γ T细胞是H. pylori感染早期主要的IL-17来源。结果提示，γ T细胞可能通过分泌IL-17参与了H. pylori感染的免疫应答。
1.6H. pylori感染过程中γ T细胞分泌IL-17依赖于IL-23的表达。
2. γ T细胞在H. pylori感染中的具体作用
2.1H. pylori分别感染野生型及γ T细胞敲除小鼠，结果显示敲除小鼠胃粘膜H.pylori定植量及组织炎症程度均显著高于野生型小鼠(P <0.05)。提示γ T细胞在H.pylori可能发挥免疫保护性作用。
2.2我们采用体外扩增的γ T细胞过继免疫TCR--/-小鼠后再感染H. pylori，检测细菌定植量和胃组织炎症的变化。与HBSS处理组相比，过继免疫组H. pylori感染后胃粘膜H. pylori定植量及组织炎症程度均显著降低(P <0.05)。结果进一步证实了γT细胞在抵御H. pylori感染定植中的保护性作用。
3. γ T细胞在H. pylori感染中的作用机制研究
3.1采用流式细胞技术分析了H. pylori感染后野生型小鼠与敲除小鼠的适应性免疫应答(Th细胞)的变化。结果显示，敲除γ T细胞后，Th17和Th22细胞的特异性免疫应答增强，而Th1和Th2型细胞免疫应答则减弱。胃粘膜组织real-time PCR结果也显示，敲除小鼠感染H. pylori后，IL-17水平在感染早期较野生型小鼠低，而在感染后期(28d)，其水平则显著升高。感染后期的IFN_(-γ)表达则明显减弱。提示，γ T细胞可能通过影响后续的适应性免疫应答参与了H. pylori感染的免疫保护效应。
3.2感染早期γ T细胞敲除小鼠胃粘膜中性粒细胞趋化相关的细胞因子及趋化因子(CXCL1, CXCL2, IL-6, GM-CSF, TNF-)水平降低。提示γ T细胞可能通过分泌IL-17诱导中性粒细胞的募集控制H. pylori早期感染的增殖扩散。
3.3分析了H. pylori感染后野生型小鼠与敲除小鼠血清及胃粘膜的IgG和IgA抗体水平。结果显示，γ T细胞敲除后，血清IgG水平无明显改变(P>0.05)，而粘膜局部的IgA水平则明显减低(P <0.05)。说明γ T细胞在粘膜局部抗体的产生过程中发挥一定作用。
3.4γ T细胞缺失后，感染小鼠胃组织中趋化因子CCL2，CCL25及CXCL1的表达与野生型小鼠相比显著升高(P <0.05)，而CCL28的表达则明显减低(P <0.05)。其他趋化因子CCL5，CCL20和CXCL2表达并无明显改变(P>0.05)。
3.5敲除γ T细胞后， H. pylori感染小鼠胃组织MMP-9的表达显著升高,MMP-7的表达则明显减低(P <0.05)，其他MMP-2，MMP-3和MMP-13的表达没有显著变化。
以上结果提示我们γ T细胞可能通过影响部分MMP及趋化因子的表达参与H.pylori感染后的免疫调控及炎症反应。
4. H. pylori感染患者外周血中γ T细胞分析
γ T细胞在H. pylori感染和未感染患者外周血中的比例并无明显变化(P>0.05)。然而，相对于H. pylori阴性患者，H. pylori感染患者外周血中产IL-17和IL-22的γ T细胞比例明显升高(P <0.05)。并且外周血中存在IFN-γ，IL-17~+或IL-22~+共表达的γ T细胞。
【主要结论】
1. H. pylori感染后可以迅速激活诱导γ T细胞应答。PP结及iIEL是H. pylori感染后较早应答的免疫场所。应答的γ T细胞主要是Vγ4亚型，并且以分泌IL-17的γT细胞为主，这类IL-17~+γ T细胞主要依赖于IL-23的表达。
2. γ T细胞在H. pylori感染中主要发挥免疫保护性作用。
3.早期应答的γ T细胞可能通过影响H. pylori特异的适应性免疫应答(细胞免疫和体液免疫)，调节部分MMP以及趋化因子的表达参与了H. pylori的定植量及炎性反应强度的控制。
4. H. pylori感染患者外周血γ T细胞比例无显著变化，但IL-17~+γ T细胞明显升高，提示γ T细胞可能通过分泌IL-17参与了机体的免疫应答。
【研究意义】
H. pylori感染的免疫机制研究以前主要集中在慢性持续性感染诱导的适应性免疫应答反应，而感染初期的固有免疫系统的作用并不完全清楚。γ T细胞作为连接固有免疫和适应性免疫系统的重要桥梁，在感染性疾病中发挥重要作用。深入了解这群细胞在H. pylori感染中的作用及免疫调控机制有助于全面阐述H. pylori感染慢性持续化致病机制，为采取正确的免疫调控方式逆转其慢性持续化进程提供新的线索。
Helicobacter pylori (H. pylori) are a Gram-negative, microaerophilic bacterium thatspecifically resides in the surface mucous layer of gastric mucosa. Epidemiological datademonstrate that there are more than50%of the population worldwide infected with H.pylori, which may cause chronic active gastritis, leading to peptic ulcer disease,mucosa-associated lymphoid tissue lymphoma and gastric adenocarcinoma. Although H.pylori infection elicits specific humoral and cellular immune responses, the bacteriumpersists and the inflammation continues for decades.
T lymphocyte plays a critical role in the pathogenesis of persistent H. pylori infection.Traditionally, two subsets of T cells have been defined: β T cells and γ T cells. To date,studies of immune responses to H. pylori have largely focused on β~+CD4~+T helper cells.However, innate immune response of γ T cells to H. pylori infection has yet to beelucidated. γ T cells are a minor T cell subset present in the spleen and lymph nodes, butrepresent a major subset within the epithelia of intestine and skin. γ T cells play animportant role in the recognition of unrestricted major histocompatibility complex (MHC)molecules and contribute to mucosal defense against invading pathogens.
H pylori have a particular tropism for the gastric epithelium, and γ T cells are mainlylocalized in mucosal tissues and abundant in the gastrointestinal tract. Thus, the relationshipbetween development and differentiation of γ T cells and the progression of H. pyloriinfection raise great concerns. Previous study reported that the percentage of γ T cellssignificantly increased in the H. pylori positive group in comparison with healthy controls.After H. pylori eradication therapy, the γ T cell count significantly decreased. However,the characteristics and role of γ T cell response in H. pylori infection have not beenelucidated. In addition, the detailed mechanism through which γ T cell regulates andaffects the system immune response is not clear.
【Objectives】
1. Try to characterize γ T cell responses to H. pylori shortly after infection of a C57BL/6mouse model.
2. Aim to elucidate the role of γ T cells in the early phase of H. pylori infection
3. To explore the mechanism through which γ T cell regulates and affects the immuneresponse to H. pylori infection
4. To analyze human peripheral blood γ T cells response in H. pylori-infected patients
【Methods】
1. C57BL/6mice were orogastrically challenged with H. pylori and lymphocytes ofspleen, Peyer's patches(PP), mesenteric lymph node(MLN) and intestinal intraepitheliallymphocytes(iIEL) were collected at the indicated times post-infection. γ T cells responseswere examined to analyze the characteristics, subsets and cytokine profiles by flowcytometry.
2. Wild-type (WT) C57BL/6and γ T cell-deficient (TCR--/-) mice was infected withH. pylori orally. The bacteria load in gastric tissue was measured with real-time PCR todetect the16s rDNA of H. pylori and the gastric inflammation was evaluated by H&Estaining. In addition, γ T cells were expanded from splenocytes in vitro and were i.v.transferred into TCR--/-mice before H. pylori infection to assay the effects of γ T cells onthe colonization and inflammation.
3. Wild-type (WT) C57BL/6and γ T cell-deficient (TCR--/-) mice was infected withH. pylori orally. Splenic lymphocytes were collected for analysis of specific Th1, Th2,Th17and Th22response by intracellular staining. Moreover, cytokines, chemokines andMMPs mRNA expression was detected by real-time PCR. Serum IgG and mucosal IgAwere evaluated by ELISA.
4. The peripheral blood mononuclear cells were isolated from25H. pylori-positivepatients with chronic antral gastritis and18H. pylori-negative healthy controls. To detectand analyze CD3, TCR γ, IFN-γ, IL-17and IL-22using flow cytometry.
【Results】
1. The characteristics of γ T cell response to H. pylori infection
1.1Following H. pylori challenge, the proportion of γ T cell in the lymphocytes ofspleen, Peyer's patches, mesenteric lymph node and intraepithelial lymphocytes wassignificantly increased. In the spleen and MLN, γ T cell was expanded from24h pi and reach a peak at48h pi, whereas in the PP and iIEL γ T cell reach its peak at24h pi. Thetime course of γ T cell responses in different organs suggests that PP and iIEL may be twoearlier sites of γ T cell priming during H. pylori infection.
1.2Purified spleen CD3~+T cells were co-cultured with viable H. pylori or fixedbacteria. Only viable H. pylori induce the expansion of γ T cell (P <0.05). The lack ofCagA or UreB could not show the obvious influences on γ T cell proliferation (P>0.05).
1.3Following H. pylori challenge, γ T cell exhibit increased CD69, CD44and CD25expression (P <0.05).
1.4Analysis of the γ T cell subsets in the spleen demonstrated that Vγ4~+cells seemedto be responsible for the rapid increase in the population of γ T cell (P <0.05). In thegastric mucosa, Vγ7were the dominant γ T cell population. After H. pylori infection, theexpression of the Vγ4gene increased.
1.5Effect of H. pylori infection on cytokine profiles of γ T cells was investigated,IL-4-, IL-10-and IL-22-producing γ T cells comprise a very small part of γ T cells and nosignificant change was observed after H. pylori infection. IFN-γ-and IL-17-producing γ Tcells were the dominant population. IFN-γ~+γ T cells did not change significantly (P>0.05),whereas the percentage of IL-17~+γ T cells significantly was increased at24h pi and reacha peak at48h, even persisted for the follow-up time points(P <0.01). At the early stage ofH. pylori infection, IL-17~+γ T cells were the major source of IL-17. In addition,IL-23-mediated signaling induced IL-17production by γ T cells.
2. The protective role of γ T cells in H. pylori infection.
2.1The colonization of H. pylori and the inflammation of gastric mucosa in the γ Tcell-deficient were significantly higher than that in the WT mice (P <0.05), suggesting thatdeletion of γ T cells might impair host defense against H. pylori infection.
2.2γ T-cell-transferred mice showed significantly lower copies of H. pylori thanthose from HBSS-treated mice (P <0.05). In addition, the mean microscopical score of γT-cell-transferred mice were significantly lower compared to HBSS-treated mice (P <0.05). These results indicate that γ T cells might increase the resistance to H. pyloriinfection.
3. The effect of γ T cells on host immune response to H. pylori infection
3.1Splenic lymphocytes from TCR--/-mice showed significantly higher Th17and Th22cell responses than those from WT mice when stimulated with H. pylori whole cellprotein or PMA/ionomycin. On the contrary, Th1and Th2cell responses were significantlyattenuated. In addition, at the early stage of infection, expression of IL-17mRNA waslower in gastric mucosa from TCR--/-mice than those of from WT mice, whereas at28d piIL-17mRNA was expressed at a higher level. IFN_(-γ)mRNA was expressed at a lower levelin the gastric mucosa of TCR--/-mice than those in WT mice. These results suggest thatlack of γ T cells might have an effect on specific Th cell responses to H. pylori infection.
3.2Decreased expression of neutrophil-inducing cytokine/chemokine in the stomachof infected TCR--/-mice
3.3Deletion of γ T cell led to attenuated production of gastric mucosal H. pylorispecific IgA (P <0.05), but it had no significant effect on the level of serum IgG (P>0.05).
3.4H. pylori infected TCR--/-mice showed significantly increase of CCL2, CXCL1and CCL25mRNA expression compared with those of infected WT mice (P <0.05).Whereas, CCL28mRNA was expressed at a lower level in comparison with that of infectedWT mice (P <0.05). Other detected chemokines, such as CCL5, CCL20and CXCL2wasnot significantly changed.
3.5Lack of γ T cells led to increased expression of MMP-9mRNA and reducedexpression of MMP-7(P <0.05). No significant change of other MMPs (MMP-2, MMP-3and MMP-13) was observed. These results imply that γ T cells may exert its effect on theH. pylori infection by enhancing or attenuating expression of chemokines and MMPs.
4. The frequency of γ T cells in H. pylori-positive patients was not significantlydifferent compared to those of healthy controls (P>0.05). However, we observed thatIL-17-producing γ T cells were one important source of IL-17in response to H. pyloriinfection. Moreover, the subsets of IL-17-and IL-22-producing, not IFN-γ-producing γ Tcells markedly increased (P <0.05).
【Conclusion】
1. H. pylori infection induced rapidly γ T cells response in the C57BL/6mousemodel. The γ T cells responses occurred earlier in the PP and iIEL than in the spleen orMLN. Vγ4~+γ T cells were responsible for the increased population of γ T cell. Moreover,IL-17produced by γ T cells was the dominant source of IL-17at the early stage of H.pylori infection. IL-23-mediated signaling induced IL-17production by γ T cells.
2. γ T cells play a protective role in H. pylori infection.
3. The role of γ T cells on H. pylori infection might be associated with alteredspecific adaptive immune response and the expression of cytokines/chemokines and MMPs.
4. γ T cells might involve human immune response to H. pylori infection via production ofIL-17.
【significance】
Previous studies largely focused on the adaptive immune response to H. pyloriinfection. Innate immune response to H. pylori infection has yet to elucidate. As a bridgebetween the innate and the adaptive immune system, γ T cells played an indispensible rolein pathogen elimination and immune regulation. A better understanding of thecharacteristics, function and regulation of γ T cells responses to H. pylori infection mayhelp us to explore novel and effective immunotherapies for gastric diseases induced by thisorganism.
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