本文選題：免疫抑制性受體 + EAE��； 參考：《第二軍醫(yī)大學》2009年博士論文

【摘要】： 在自身免疫性疾病治療,骨髓移植、器官移植日益發(fā)展的今天,對免疫耐受產生的機制以及人工誘導免疫耐受方法的研究受到了廣泛的關注。而免疫抑制性受體在免疫耐受中的作用是該領域的熱門課題。最近的研究證實,免疫抑制性受體在細胞生長、增殖、分化過程中發(fā)揮重要負調控功能。此外,也有越來越多的研究發(fā)現該類受體能通過轉導抑制性信號,在免疫耐受的建立和維持中發(fā)揮重要作用。對抑制性受體參與免疫保護機制的研究有利于闡明許多自身免疫性疾病的免疫病因,同時對腫瘤免疫和移植免疫等研究也具有重要意義。 本室曾通過大規(guī)模隨機基因測序分別從人和小鼠DCs的cDNA文庫中獲得一條含有C型凝集素樣結構域(C-type lectin-like domain,CTLD)的新核苷酸序列,命名為殺傷細胞凝集素樣受體L(1Killer cell Lectin-like Receptors L1,KLRL1)。前期對KLRL1的研究發(fā)現,KLRL1在新鮮分離的DCs、NK細胞、CD4+、CD8+T細胞和單核細胞系中均有不同程度表達,并且其序列胞外段中包含一個免疫受體酪氨酸相關的抑制性基序(ITIM),磷酸化后能結合SHP-1和SHP-2,提示該分子可能作為抑制性受體發(fā)揮負相調控功能。本實驗室前期對 KLRL1的功能研究還發(fā)現,KLRL1在DCs上的表達水平隨DCs成熟而下降,尤其在LPS刺激成熟后下降尤為顯著。除此之外,組成性表達mKLRL1的DCs經LPS刺激后表現為吞噬功能增強,抗原提呈能力減弱。以上這些結果均表明,KLRL1作為一種抑制性受體,在DCs成熟過程中具有重要的作用,并參與調控耐受性DCs的生物學功能。DCs的成熟狀態(tài)在一定程度上決定了免疫反應的結局,與機體的免疫激活或免疫耐受之間存在密切關系�；贙LRL1分子在DCs成熟過程中的表達水平變化及前期對該受體生物學功能的研究,我們推測免疫抑制性受體KLRL1的表達水平很可能對DCs誘導的免疫應答或免疫耐受有重要意義。因此,在本研究中,我們進一步觀察了免疫抑制性受體KLRL1體內參與誘導特異性免疫耐受的作用,通過將KLRL1基因轉染至DCs使之高表達并給予抗原刺激和活化后腹腔注射免疫小鼠,發(fā)現與對照組小鼠相比,對隨后的實驗性自身免疫性腦脊髓炎(EAE)誘導有明顯保護作用。隨后我們對免疫抑制性受體KLRL1發(fā)揮其負相調控功能的分子和信號機制也進行了探究。 (一)免疫抑制性受體KLRL1參與誘導體內特異性免疫耐受的研究 本部分中,我們通過建立小鼠實驗性自身免疫性腦脊髓炎(EAE)模型,研究了組成性表達mKLRL1的DCs免疫小鼠后對隨后EAE誘導的保護效果,探討了該免疫抑制性受體誘導特異性免疫耐受的作用。 我們以MOG35-55多肽作為抗原,輔以腹腔注射百日咳毒素,成功地建立C57BL/6小鼠的EAE模型。其中抗原肽誘導建立的EAE組小鼠發(fā)病率達到95%,平均臨床打分為3.16±0.79,并且該EAE模型為復發(fā)-緩解型,在疾病過程中具有間歇期和不同程度的恢復。隨后我們觀察了組成性表達mKLRL1分子的DCs對EAE誘導的保護效果。取培養(yǎng)至第四天的骨髓細胞來源的未成熟樹突狀細胞,通過Ad-KLRL1重組腺病毒轉染得到組成性表達mKLRL1的DCs,用LPS刺激活化后負載髓鞘少突膠質細胞糖蛋白MOG35-55抗原肽,通過腹腔注射免疫正常C57BL/6小鼠,免疫后第二天在各組小鼠中誘導EAE。我們發(fā)現與對照組小鼠相比,組成性表達mKLRL1的DCs免疫組小鼠的發(fā)病時間明顯推遲,最長一次推遲27天;發(fā)病率也明顯下降;此外,與對照組比較,臨床神經功能評分也有所改善。以上結果都顯示,組成性表達mKLRL1分子的DCs能使EAE誘導的發(fā)病時間推遲,降低小鼠的發(fā)病數量,改善小鼠的臨床癥狀,對MOG35-55抗原肽誘導的EAE具有保護作用。為了進一步從體內驗證組成性表達mKLRL1的DCs免疫后對EAE誘導的保護效果,我們也檢測了體內MOG35-55特異性淋巴細胞的增殖情況。抗原免疫后第14天,我們取各免疫組小鼠的腋下淋巴結和脾臟,發(fā)現對照組小鼠脾臟與組成性表達mKLRL1的DCs免疫組小鼠脾臟相比明顯增大。通過進一步檢測MOG35-55特異性淋巴細胞的增殖,我們發(fā)現,MOG35-55多肽抗原刺激對照組淋巴結細胞的增殖作用明顯,而刺激組成性表達mKLRL1的DCs免疫組(Ad-KLRL1)淋巴結細胞的增殖反應很弱。以上結果均提示,組成性表達mKLRL1的DCs免疫小鼠后,對隨后EAE誘導具有保護作用,提示KLRL1分子可能參與體內特異性免疫耐受的建立。 (二)免疫抑制性受體KLRL1調控耐受性DCs功能的分子和信號機制研究 以往研究發(fā)現,用KLRL1重組腺病毒轉染DCs后再用LPS刺激,IL-10的分泌量顯著增加。IL-10是一種重要的具有免疫負調節(jié)作用的細胞因子。是否免疫抑制性受體KLRL1能通過調節(jié)LPS刺激后DCs中IL-10的分泌水平,進而影響了機體的免疫應答呢?圍繞該線索,我們進一步對抑制性受體KLRL1負相調控DCs功能的分子和信號機制進行了探究。 為了研究IL-10在KLRL1發(fā)揮負相調控功能過程中的作用,我們在隨后的研究中比較了組成性表達mKLRL1的正常小鼠DCs和組成性表達mKLRL1的IL-10基因敲除小鼠DCs的相關功能變化,以分析IL-10在抑制性受體KLRL1調控耐受性DCs功能過程中的作用。我們首先檢測了IL-10對KLRL1調控DCs吞噬能力的影響。用KLRL1重組腺病毒轉染DCs后再經LPS刺激24小時,隨后用OVA-FITC模擬外來抗原,采用FACS檢測DCs吞噬外來抗原的能力。發(fā)現組成性表達mKLRL1的正常小鼠來源DCs,較對照病毒組相比,在LPS刺激后仍保持很強的吞噬能力;而組成性表達mKLRL1的IL-10基因敲除小鼠DCs的吞噬能力與對照組無顯著差異,這一結果提示IL-10在KLRL1調控DCs吞噬能力的過程中發(fā)揮重要作用。由于KLRL1的表達水平隨DCs分化成熟而明顯下降,我們推測KLRL1可能參與調控DCs成熟過程中共刺激分子的表達。因此,我們也觀察了組成性表達mKLRL1的DCs經LPS刺激后的表型變化。結果顯示,與對照組相比,組成性表達mKLRL1的正常小鼠來源DCs經LPS刺激后,表面共刺激分子CD80、CD86的表達水平降低,但CD40變化不明顯。而組成性表達mKLRL1的IL-10基因敲除小鼠來源DCs可以在一定程度上逆轉CD80、CD86的表達水平。這一結果提示,IL-10對KLRL1負調控DCs表面一些共刺激分子的表達有重要作用。我們也檢測了IL-10在KLRL1調控DCs抗原提呈能力過程的作用。發(fā)現經LPS刺激成熟后, KLRL1修飾的正常小鼠來源的DCs,與對照病毒組相比,其刺激抗原特異性T細胞增殖的能力明顯下降;而KLRL1修飾的IL-10基因敲除小鼠來源的DCs與對照病毒組相比,刺激T細胞增殖的能力卻無明顯變化。提示IL-10參與KLRL1對DCs抗原提呈能力的負調控過程。以上結果均提示,IL-10在KLRL1調控耐受性DCs的過程中發(fā)揮重要作用,可能是免疫抑制性受體KLRL1發(fā)揮功能的一個重要效應分子。 由于以往研究中還發(fā)現,組成性表達mKLRL1的DCs經LPS刺激后分泌TNF-α的水平明顯下降,而IL-10對LPS刺激引起的大部分炎性細胞因子的分泌均有抑制作用,因此我們在本研究中也對其他一些重要細胞因子的分泌進行了檢測。結果顯示,組成性表達mKLRL1的樹突狀細胞經LPS刺激后,分泌TNF-α的水平明顯下降,而分泌IL-6,IL-1β和IL-12 p70等細胞因子的水平與對照病毒組相比,均無顯著差異。由于TNF-α對DCs的成熟具有促進作用,因此這一結果也提示,抑制性受體KLRL1可能通過調節(jié)DCs高分泌IL-10,同時抑制TNF-α的分泌,從而負相調控免疫應答。 既然高分泌IL-10對組成性表達mKLRL1的DCs發(fā)揮免疫調控功能有如此重要的作用,那么免疫抑制性受體KLRL1是通過什么途徑調控DCs高分泌IL-10的呢?此外,LPS刺激能導致KLRL1表達水平下降,受體KLRL1與TLR4信號通路之間又存在什么樣的調控關系呢?我們隨后對以上機制也進行了分析。我們首先檢測了組成性表達mKLRL1的DCs高分泌IL-10與LPS刺激之間的關系。發(fā)現組成性表達mKLRL1的DCs高分泌IL-10是依賴于LPS刺激作用的。這也表明KLRL1可能通過調控TLR4信號轉導而影響IL-10的分泌。我們隨后進一步對組成性表達mKLRL1的DCs中幾種重要信號通路的活化情況進行了檢測。我們首先檢測了TLR4受體的表達情況。發(fā)現無論在LPS刺激前或刺激后,過表達KLRL1分子對DCs表面的TLR4表達水平無影響。提示KLRL1對TLR4信號通路的調控作用并不是通過直接調節(jié)TLR4受體表達實現的。隨后我們又檢測了TLR4下游的MAPKs信號途徑,包括信號分子JNK1/2、ERK1/2、p38的磷酸化水平變化。我們發(fā)現組成性表達mKLRL1的DCs與對照組相比,ERK1/2和p38分子的磷酸化水平無明顯變化,而JNK1/2分子的磷酸化水平在LPS刺激20min時被明顯抑制,對JNK1/2上游激酶MKK4的檢測也得到一致結果,這提示KLRL1發(fā)揮其負調控作用可能與JNK信號途徑有關。此外,組成性表達mKLRL1的DCs中的磷酸化IκBα的表達水平在LPS刺激后降低,且上游IKKα/β激酶的磷酸化水平也有相同變化,提示KLRL1分子在DCs中過表達后能有效抑制TLR4下游NF-κB信號途徑的活化。這可能與組成性表達mKLRL1的DCs分泌TNF-α下降密切相關。我們也檢測了PI3K-Akt通路的活化情況,結果顯示,組成性表達mKLRL1的DCs與對照病毒組相比,其磷酸化Akt的表達水平無顯著變化。 為了從反方面驗證免疫抑制性受體KLRL1對以上信號通路的調控功能,我們又利用KLRL1干擾腺病毒在Raw264.7細胞中進行了檢測。我們發(fā)現,干擾KLRL1表達的RAW264.7細胞經LPS刺激后, JNK1/2及其上游激酶MKK4的磷酸化水平均有明顯升高,而ERK1/2和p38磷酸化水平與對照組相比無明顯差異。這也從反方面提示,KLRL1發(fā)揮其負調控功能可能與JNK信號途徑有關。此外,我們也檢測到干擾KLRL1表達的RAW細胞中NF-κB信號通路的活化增強,進一步提示了KLRL1對NF-κB信號通路具有負相調控作用。 綜上所述,我們對免疫抑制性受體KLRL1體內誘導免疫耐受的作用進行了研究,發(fā)現組成性表達mKLRL1分子的DCs免疫小鼠對隨后EAE誘導具有保護作用。提示免疫抑制性受體KLRL1可能參與誘導機體產生特異性免疫耐受。隨后我們對KLRL1發(fā)揮負調控功能的分子和信號機制進行了分析,發(fā)現IL-10對KLRL1調控耐受性DCs的吞噬能力,共刺激分子表達及抗原提呈等功能具有重要意義,可能是KLRL1發(fā)揮作用的一個重要效應分子。通過進一步對信號通路活化的檢測,我們發(fā)現組成性表達mKLRL1的DCs經LPS刺激后, JNK和NF-κB途徑的活化受到明顯抑制,這可能與組成性表達mKLRL1分子的DCs分泌TNF-α下降相關。盡管如此,我們并沒有找到一條組成性表達mKLRL1的DCs經LPS刺激后明顯活化的信號通路,組成性表達mKLRL1的DCs是通過什么途徑高分泌IL-10的呢?其中的機制還在進一步研究中。
[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.

【學位授予單位】：第二軍醫(yī)大學
【學位級別】：博士
【學位授予年份】：2009
【分類號】：R392

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