新型免疫抑制性受体KLRL1在免疫耐受中的作用及其相关机制研究

发布时间：2018-05-11 16:03

  本文选题：免疫抑制性受体 + EAE　； 参考：《第二军医大学》2009年博士论文

【摘要】： 在自身免疫性疾病治疗,骨髓移植、器官移植日益发展的今天,对免疫耐受产生的机制以及人工诱导免疫耐受方法的研究受到了广泛的关注。而免疫抑制性受体在免疫耐受中的作用是该领域的热门课题。最近的研究证实,免疫抑制性受体在细胞生长、增殖、分化过程中发挥重要负调控功能。此外,也有越来越多的研究发现该类受体能通过转导抑制性信号,在免疫耐受的建立和维持中发挥重要作用。对抑制性受体参与免疫保护机制的研究有利于阐明许多自身免疫性疾病的免疫病因,同时对肿瘤免疫和移植免疫等研究也具有重要意义。 本室曾通过大规模随机基因测序分别从人和小鼠DCs的cDNA文库中获得一条含有C型凝集素样结构域(C-type lectin-like domain,CTLD)的新核苷酸序列,命名为杀伤细胞凝集素样受体L(1Killer cell Lectin-like Receptors L1,KLRL1)。前期对KLRL1的研究发现,KLRL1在新鲜分离的DCs、NK细胞、CD4+、CD8+T细胞和单核细胞系中均有不同程度表达,并且其序列胞外段中包含一个免疫受体酪氨酸相关的抑制性基序(ITIM),磷酸化后能结合SHP-1和SHP-2,提示该分子可能作为抑制性受体发挥负相调控功能。本实验室前期对 KLRL1的功能研究还发现,KLRL1在DCs上的表达水平随DCs成熟而下降,尤其在LPS刺激成熟后下降尤为显著。除此之外,组成性表达mKLRL1的DCs经LPS刺激后表现为吞噬功能增强,抗原提呈能力减弱。以上这些结果均表明,KLRL1作为一种抑制性受体,在DCs成熟过程中具有重要的作用,并参与调控耐受性DCs的生物学功能。DCs的成熟状态在一定程度上决定了免疫反应的结局,与机体的免疫激活或免疫耐受之间存在密切关系。基于KLRL1分子在DCs成熟过程中的表达水平变化及前期对该受体生物学功能的研究,我们推测免疫抑制性受体KLRL1的表达水平很可能对DCs诱导的免疫应答或免疫耐受有重要意义。因此,在本研究中,我们进一步观察了免疫抑制性受体KLRL1体内参与诱导特异性免疫耐受的作用,通过将KLRL1基因转染至DCs使之高表达并给予抗原刺激和活化后腹腔注射免疫小鼠,发现与对照组小鼠相比,对随后的实验性自身免疫性脑脊髓炎(EAE)诱导有明显保护作用。随后我们对免疫抑制性受体KLRL1发挥其负相调控功能的分子和信号机制也进行了探究。 (一)免疫抑制性受体KLRL1参与诱导体内特异性免疫耐受的研究 本部分中,我们通过建立小鼠实验性自身免疫性脑脊髓炎(EAE)模型,研究了组成性表达mKLRL1的DCs免疫小鼠后对随后EAE诱导的保护效果,探讨了该免疫抑制性受体诱导特异性免疫耐受的作用。 我们以MOG35-55多肽作为抗原,辅以腹腔注射百日咳毒素,成功地建立C57BL/6小鼠的EAE模型。其中抗原肽诱导建立的EAE组小鼠发病率达到95%,平均临床打分为3.16±0.79,并且该EAE模型为复发-缓解型,在疾病过程中具有间歇期和不同程度的恢复。随后我们观察了组成性表达mKLRL1分子的DCs对EAE诱导的保护效果。取培养至第四天的骨髓细胞来源的未成熟树突状细胞,通过Ad-KLRL1重组腺病毒转染得到组成性表达mKLRL1的DCs,用LPS刺激活化后负载髓鞘少突胶质细胞糖蛋白MOG35-55抗原肽,通过腹腔注射免疫正常C57BL/6小鼠,免疫后第二天在各组小鼠中诱导EAE。我们发现与对照组小鼠相比,组成性表达mKLRL1的DCs免疫组小鼠的发病时间明显推迟,最长一次推迟27天;发病率也明显下降;此外,与对照组比较,临床神经功能评分也有所改善。以上结果都显示,组成性表达mKLRL1分子的DCs能使EAE诱导的发病时间推迟,降低小鼠的发病数量,改善小鼠的临床症状,对MOG35-55抗原肽诱导的EAE具有保护作用。为了进一步从体内验证组成性表达mKLRL1的DCs免疫后对EAE诱导的保护效果,我们也检测了体内MOG35-55特异性淋巴细胞的增殖情况。抗原免疫后第14天,我们取各免疫组小鼠的腋下淋巴结和脾脏,发现对照组小鼠脾脏与组成性表达mKLRL1的DCs免疫组小鼠脾脏相比明显增大。通过进一步检测MOG35-55特异性淋巴细胞的增殖,我们发现,MOG35-55多肽抗原刺激对照组淋巴结细胞的增殖作用明显,而刺激组成性表达mKLRL1的DCs免疫组(Ad-KLRL1)淋巴结细胞的增殖反应很弱。以上结果均提示,组成性表达mKLRL1的DCs免疫小鼠后,对随后EAE诱导具有保护作用,提示KLRL1分子可能参与体内特异性免疫耐受的建立。 (二)免疫抑制性受体KLRL1调控耐受性DCs功能的分子和信号机制研究 以往研究发现,用KLRL1重组腺病毒转染DCs后再用LPS刺激,IL-10的分泌量显著增加。IL-10是一种重要的具有免疫负调节作用的细胞因子。是否免疫抑制性受体KLRL1能通过调节LPS刺激后DCs中IL-10的分泌水平,进而影响了机体的免疫应答呢?围绕该线索,我们进一步对抑制性受体KLRL1负相调控DCs功能的分子和信号机制进行了探究。 为了研究IL-10在KLRL1发挥负相调控功能过程中的作用,我们在随后的研究中比较了组成性表达mKLRL1的正常小鼠DCs和组成性表达mKLRL1的IL-10基因敲除小鼠DCs的相关功能变化,以分析IL-10在抑制性受体KLRL1调控耐受性DCs功能过程中的作用。我们首先检测了IL-10对KLRL1调控DCs吞噬能力的影响。用KLRL1重组腺病毒转染DCs后再经LPS刺激24小时,随后用OVA-FITC模拟外来抗原,采用FACS检测DCs吞噬外来抗原的能力。发现组成性表达mKLRL1的正常小鼠来源DCs,较对照病毒组相比,在LPS刺激后仍保持很强的吞噬能力;而组成性表达mKLRL1的IL-10基因敲除小鼠DCs的吞噬能力与对照组无显著差异,这一结果提示IL-10在KLRL1调控DCs吞噬能力的过程中发挥重要作用。由于KLRL1的表达水平随DCs分化成熟而明显下降,我们推测KLRL1可能参与调控DCs成熟过程中共刺激分子的表达。因此,我们也观察了组成性表达mKLRL1的DCs经LPS刺激后的表型变化。结果显示,与对照组相比,组成性表达mKLRL1的正常小鼠来源DCs经LPS刺激后,表面共刺激分子CD80、CD86的表达水平降低,但CD40变化不明显。而组成性表达mKLRL1的IL-10基因敲除小鼠来源DCs可以在一定程度上逆转CD80、CD86的表达水平。这一结果提示,IL-10对KLRL1负调控DCs表面一些共刺激分子的表达有重要作用。我们也检测了IL-10在KLRL1调控DCs抗原提呈能力过程的作用。发现经LPS刺激成熟后, KLRL1修饰的正常小鼠来源的DCs,与对照病毒组相比,其刺激抗原特异性T细胞增殖的能力明显下降;而KLRL1修饰的IL-10基因敲除小鼠来源的DCs与对照病毒组相比,刺激T细胞增殖的能力却无明显变化。提示IL-10参与KLRL1对DCs抗原提呈能力的负调控过程。以上结果均提示,IL-10在KLRL1调控耐受性DCs的过程中发挥重要作用,可能是免疫抑制性受体KLRL1发挥功能的一个重要效应分子。 由于以往研究中还发现,组成性表达mKLRL1的DCs经LPS刺激后分泌TNF-α的水平明显下降,而IL-10对LPS刺激引起的大部分炎性细胞因子的分泌均有抑制作用,因此我们在本研究中也对其他一些重要细胞因子的分泌进行了检测。结果显示,组成性表达mKLRL1的树突状细胞经LPS刺激后,分泌TNF-α的水平明显下降,而分泌IL-6,IL-1β和IL-12 p70等细胞因子的水平与对照病毒组相比,均无显著差异。由于TNF-α对DCs的成熟具有促进作用,因此这一结果也提示,抑制性受体KLRL1可能通过调节DCs高分泌IL-10,同时抑制TNF-α的分泌,从而负相调控免疫应答。 既然高分泌IL-10对组成性表达mKLRL1的DCs发挥免疫调控功能有如此重要的作用,那么免疫抑制性受体KLRL1是通过什么途径调控DCs高分泌IL-10的呢?此外,LPS刺激能导致KLRL1表达水平下降,受体KLRL1与TLR4信号通路之间又存在什么样的调控关系呢?我们随后对以上机制也进行了分析。我们首先检测了组成性表达mKLRL1的DCs高分泌IL-10与LPS刺激之间的关系。发现组成性表达mKLRL1的DCs高分泌IL-10是依赖于LPS刺激作用的。这也表明KLRL1可能通过调控TLR4信号转导而影响IL-10的分泌。我们随后进一步对组成性表达mKLRL1的DCs中几种重要信号通路的活化情况进行了检测。我们首先检测了TLR4受体的表达情况。发现无论在LPS刺激前或刺激后,过表达KLRL1分子对DCs表面的TLR4表达水平无影响。提示KLRL1对TLR4信号通路的调控作用并不是通过直接调节TLR4受体表达实现的。随后我们又检测了TLR4下游的MAPKs信号途径,包括信号分子JNK1/2、ERK1/2、p38的磷酸化水平变化。我们发现组成性表达mKLRL1的DCs与对照组相比,ERK1/2和p38分子的磷酸化水平无明显变化,而JNK1/2分子的磷酸化水平在LPS刺激20min时被明显抑制,对JNK1/2上游激酶MKK4的检测也得到一致结果,这提示KLRL1发挥其负调控作用可能与JNK信号途径有关。此外,组成性表达mKLRL1的DCs中的磷酸化IκBα的表达水平在LPS刺激后降低,且上游IKKα/β激酶的磷酸化水平也有相同变化,提示KLRL1分子在DCs中过表达后能有效抑制TLR4下游NF-κB信号途径的活化。这可能与组成性表达mKLRL1的DCs分泌TNF-α下降密切相关。我们也检测了PI3K-Akt通路的活化情况,结果显示,组成性表达mKLRL1的DCs与对照病毒组相比,其磷酸化Akt的表达水平无显著变化。 为了从反方面验证免疫抑制性受体KLRL1对以上信号通路的调控功能,我们又利用KLRL1干扰腺病毒在Raw264.7细胞中进行了检测。我们发现,干扰KLRL1表达的RAW264.7细胞经LPS刺激后, JNK1/2及其上游激酶MKK4的磷酸化水平均有明显升高,而ERK1/2和p38磷酸化水平与对照组相比无明显差异。这也从反方面提示,KLRL1发挥其负调控功能可能与JNK信号途径有关。此外,我们也检测到干扰KLRL1表达的RAW细胞中NF-κB信号通路的活化增强,进一步提示了KLRL1对NF-κB信号通路具有负相调控作用。 综上所述,我们对免疫抑制性受体KLRL1体内诱导免疫耐受的作用进行了研究,发现组成性表达mKLRL1分子的DCs免疫小鼠对随后EAE诱导具有保护作用。提示免疫抑制性受体KLRL1可能参与诱导机体产生特异性免疫耐受。随后我们对KLRL1发挥负调控功能的分子和信号机制进行了分析,发现IL-10对KLRL1调控耐受性DCs的吞噬能力,共刺激分子表达及抗原提呈等功能具有重要意义,可能是KLRL1发挥作用的一个重要效应分子。通过进一步对信号通路活化的检测,我们发现组成性表达mKLRL1的DCs经LPS刺激后, JNK和NF-κB途径的活化受到明显抑制,这可能与组成性表达mKLRL1分子的DCs分泌TNF-α下降相关。尽管如此,我们并没有找到一条组成性表达mKLRL1的DCs经LPS刺激后明显活化的信号通路,组成性表达mKLRL1的DCs是通过什么途径高分泌IL-10的呢?其中的机制还在进一步研究中。
[Abstract]:Today, in the treatment of autoimmune diseases, bone marrow transplantation, and organ transplantation, the mechanism of immune tolerance and the study of artificial immune tolerance are widely concerned. The role of immunosuppressive receptors in immune tolerance is a hot topic in this field. Recent studies have confirmed that immunosuppression is subject to immunosuppression. Body plays an important negative regulatory function in the process of cell growth, proliferation and differentiation. In addition, more and more studies have found that this kind of receptor can play an important role in the establishment and maintenance of immune tolerance by transducing inhibitory signals. It is also important for the study of immune etiology and tumor immunity and transplantation immunity.
We have obtained a new nucleotide sequence containing the C-type lectin-like domain (CTLD) domain (C-type lectin-like domain, CTLD) from the human and mouse DCs library by large-scale random gene sequencing, and named the killer cell lectin like receptor L (1Killer cell Lectin-like Receptors). 1 in fresh separated DCs, NK cells, CD4+, CD8+T cells and mononuclear cell lines, the expression of a receptor tyrosine related inhibitory motif (ITIM) is contained in the outer segment of its sequence, and phosphorylated with SHP-1 and SHP-2, suggesting that the molecule can play a negative regulatory function as a suppressor receptor. Prophase
The functional study of KLRL1 also found that the expression level of KLRL1 on DCs decreased with the maturity of DCs, especially when LPS stimulated maturity. In addition, the DCs of the constituent mKLRL1 was stimulated by LPS to enhance the phagocytic function and the antigen presentation ability weakened. These results all showed that KLRL1 was a kind of inhibitory receptor. DCs plays an important role in the maturation process, and participates in the biological function of the regulation of the biological function of tolerance DCs. The mature state of.DCs determines the outcome of the immune response to a certain extent. There is a close relationship between the immune activation and immune tolerance of the body. The changes in the expression level of the KLRL1 molecule in the mature process of DCs and the early stage of the receptor to the receptor We speculate that the expression level of the immunosuppressive receptor KLRL1 is very important for DCs induced immune response or immune tolerance. Therefore, in this study, we further observed the role of the immunosuppressive receptor KLRL1 in inducing specific immune tolerance by transfecting the KLRL1 gene into DCs The high expression and immunization of mice with antigen stimulation and activation were found to have obvious protective effects on the subsequent experimental autoimmune encephalomyelitis (EAE) induction in mice compared with the control group. Then we also explored the molecular and signal mechanisms of the immunosuppressive receptor KLRL1 in its negative regulatory function.
(1) immunosuppressive receptor KLRL1 is involved in the induction of specific immune tolerance in vivo.
In this section, we studied the protective effect of DCs immunized mice on the subsequent EAE induced by DCs immunized mice, and explored the effect of the immunosuppressive receptor on the induction of specific immune tolerance by establishing an experimental autoimmune encephalomyelitis (EAE) model in mice.
We successfully established the EAE model of C57BL/6 mice with MOG35-55 peptide as an antigen supplemented by intraperitoneal injection of pertussis toxin, in which the incidence of C57BL/6 mice induced by antigenic peptide was 95%, the average clinical score was 3.16 + 0.79, and the EAE model was a relapse remission type, with a intermittent and varying degree of recovery in the course of the disease. Then we observed the protective effect of DCs on EAE induced by the constituent expression of mKLRL1. The immature dendritic cells derived from bone marrow cells were cultured for fourth days, and DCs was transfected through Ad-KLRL1 recombinant adenovirus, and the activated myelin oligodendrocyte glycoprotein MOG35-55 antigen peptide was stimulated by LPS. After immunizing normal C57BL/6 mice by intraperitoneal injection, EAE. was induced in each group second days after immunization. We found that compared with the control group, the onset time of the DCs immune group of the mKLRL1 group was delayed obviously, the longest time was delayed for 27 days, and the incidence was obviously lower. In addition, the clinical neurological score was compared with the control group. The above results have also shown that the DCs of the constituent expression of mKLRL1 molecules can delay the onset of EAE induced disease, reduce the number of mice, improve the clinical symptoms of mice, and protect the EAE induced by the MOG35-55 antigen peptide. In order to further verify the EAE induced by the DCs immunization of the constituent expression of mKLRL1 from the body, the protection of EAE is guaranteed. We also detected the proliferation of MOG35-55 specific lymphocytes in the body. After fourteenth days of antigen immunization, we took the subaxillary lymph nodes and spleen of the mice in the immunization groups, and found that the spleen of the control group was significantly increased in the spleen of the DCs immune group that expressed mKLRL1 in the mice. By further detection of the specific lymph nodes of the MOG35-55 specific lymph nodes. Cell proliferation, we found that MOG35-55 polypeptide antigen stimulated the proliferation of the lymph node cells in the control group, and the proliferation response of the DCs immune group (Ad-KLRL1) lymph node cells stimulated by the constituent expression of mKLRL1 was very weak. All of these results suggested that the DCs immunized mice with the constituent expression of mKLRL1 had a protective effect on the subsequent EAE induction. KLRL1 molecules may be involved in the establishment of specific immune tolerance in vivo.
(two) molecular and signaling mechanisms of the immunosuppressive receptor KLRL1 regulating the function of DCs.
Previous studies have found that the KLRL1 recombinant adenovirus transfected to DCs was stimulated by LPS, and the secretion of IL-10 was significantly increased by.IL-10 as an important cytokine with negative immuno regulation. Is immunosuppressive receptor KLRL1 can affect the immune response of the body by regulating the level of IL-10 secretion in DCs after LPS stimulation? We further explored the molecular and signaling mechanisms of the inhibitory receptor KLRL1 negatively regulating DCs function.
In order to study the role of IL-10 in KLRL1 play a negative regulatory function, we compared the functional changes of the normal mouse DCs and the IL-10 gene knockout DCs in the constituent expression mKLRL1 of mKLRL1 in the subsequent study, in order to analyze the role of IL-10 in the function of the inhibitory receptor KLRL1 to regulate the function of the tolerance DCs. We first detected the effect of IL-10 on the phagocytosis of DCs by KLRL1. After transfection of DCs with KLRL1 recombinant adenovirus, DCs was stimulated by LPS for 24 hours, then the external antigen was simulated with OVA-FITC, and FACS was used to detect the ability to phagocyst the foreign antigen by DCs. The phagocytosis of the IL-10 gene knockout mice with mKLRL1 was not significantly different from that of the control group. This result suggests that IL-10 plays an important role in the process of KLRL1 regulating the phagocytosis of DCs. As the expression level of KLRL1 decreases with the maturation of DCs, we speculate that KLRL1 may be involved. We also observed the expression of molecules in the regulation of DCs maturation. Therefore, we also observed the phenotypic changes of the LPS stimulated by DCs, which expressed mKLRL1. The results showed that, compared with the control group, the normal mouse source of the constituent mKLRL1 was stimulated by LPS, and the expression level of the surface costimulatory molecule CD80 and CD86 decreased, but the CD40 changes were not obvious. The IL-10 gene knockout mouse derived from mKLRL1 can reverse CD80, CD86 expression level to a certain extent. This result suggests that IL-10 plays an important role in the negative regulation of KLRL1 negative regulation on the expression of some co stimulators on the DCs surface. We also detected the role of IL-10 in KLRL1 regulation of DCs antigen presentation ability process. After the stimulation of maturity, the DCs of normal mice derived from KLRL1 modified, compared with the control virus group, significantly decreased the ability to stimulate the proliferation of antigen specific T cells, while the DCs of the KLRL1 modified IL-10 gene knockout mice had no significant changes in the ability to stimulate the proliferation of T cells compared with the control virus group. It suggested that IL-10 participated in KLRL1 against DCs antigen. These results suggest that IL-10 plays an important role in the KLRL1 regulation of tolerance DCs, and may be an important effector of the function of the immunosuppressive receptor KLRL1.
As a result of previous studies, the level of TNF- alpha secreted by the constituent expression of mKLRL1 is significantly decreased after LPS stimulation, and IL-10 has inhibitory effect on the secretion of most of the inflammatory cytokines caused by LPS stimulation. Therefore, we also detected the secretion of other important cytokines in this study. The level of TNF- alpha secreted by LPS stimulated by sex expression mKLRL1 was significantly decreased, while the levels of IL-6, IL-1 beta and IL-12 p70 were not significantly different from those of the control virus group. As TNF- a promoted the maturation of DCs, this fruit also suggested that the inhibitory receptor KLRL1 may be regulated by DCs. High secretion of IL-10 and inhibition of TNF- secretion results in a negative regulation of immune response.
Since the hypersecreting IL-10 plays such an important role in the immune regulatory function of the DCs expressing mKLRL1, then what is the way that the immunosuppressive receptor KLRL1 regulates the DCs hypersecretion of IL-10? In addition, the LPS stimulation can lead to a decrease in the level of KLRL1 expression, and what regulation exists between the receptor KLRL1 and the TLR4 signaling pathway. We then analyzed the above mechanism. We first detected the relationship between the DCs hypersecretory IL-10 of the constituent expression mKLRL1 and the LPS stimulation. It was found that the DCs hypersecretory IL-10 consisting of mKLRL1 was dependent on LPS stimulation. This also indicates that KLRL1 may affect IL-10 secretion by regulating TLR4 signal transduction. We then further examined the activation of several important signaling pathways in the constituent expression of mKLRL1 DCs. We first detected the expression of TLR4 receptors. It was found that the overexpression of KLRL1 molecules had no effect on the TLR4 expression on the DCs surface before or after the stimulation of LPS. It suggested the regulation of KLRL1 on the TLR4 signaling pathway. We did not directly regulate the expression of the TLR4 receptor. Then we detected the MAPKs signal pathway in the downstream of TLR4, including the phosphorylation level of the signal molecules JNK1/2, ERK1/2, p38. We found that the DCs of the constituent expression mKLRL1 has no significant change in the phosphorylation level of the ERK1/2 and p38 molecules compared with the control group, while the JNK1/2 molecule is phosphorous. The acidification level was obviously suppressed when LPS stimulated 20min, and the detection of the upstream kinase MKK4 of JNK1/2 was also consistent, which suggested that KLRL1 play its negative regulatory role with the JNK signaling pathway. In addition, the expression level of the phosphorylated I kappa B alpha in the DCs of the constituent expression mKLRL1 decreased after LPS stimulation, and the upstream IKK alpha / beta kinase was phosphoric acid. The transformation level also has the same changes, suggesting that KLRL1 molecules can effectively inhibit the activation of NF- kappa B signaling pathway in the downstream of TLR4 after overexpression in DCs. This may be closely related to the decline in the DCs secretion of mKLRL1 in the DCs secretion. We also detected the activation of the PI3K-Akt pathway. The results showed that the DCs of the constituent expression mKLRL1 was and the control of the virus group. There was no significant change in the expression level of its phosphorylated Akt.
In order to verify the regulatory function of the immunosuppressive receptor KLRL1 on the above signaling pathway, we also detected the KLRL1 interfering adenovirus in Raw264.7 cells. We found that the phosphorylation level of JNK1/2 and its upstream kinase MKK4 increased significantly after LPS stimulated RAW264.7 cells, while ERK1/2 and its upstream kinase MKK4 were significantly increased. There is no significant difference in the level of phosphorylation of p38 compared with the control group. This also suggests that the negative regulatory function of KLRL1 may be related to the JNK signaling pathway. In addition, we also detected the activation of the NF- kappa B signaling pathway in RAW cells that interfered with KLRL1 expression.

【学位授予单位】：第二军医大学
【学位级别】：博士
【学位授予年份】：2009
【分类号】：R392

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