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Immunoregulation
• Normal anti-infection anti-tumour
• Abnormal Auto-immune disease Tumour Persistent infection Allergy
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Regulation of immunological milecules
Immunoregulation mediated by immune cellsRegulation by by other mechanism
Immunoregulation
免疫分子的免疫调节作用
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Negative regulation of Ab production by Inhibitory receptor FcRII-BNegative regulation of Ab production by Inhibitory receptor FcRII-B
Interfere B cell signaling
BCR (mIgM)抗 BCR 抗体 Ag-Ab complex
FcRII-B FcRII-B
ITIM ITIM
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Regulation by idiotypes and anti-idiotypic antibodies Antibodies formed against Ag-binding sites of an Ab are called anti-idiotypic antibodies, and are capable of influencing the outcome of an immune response. Id and AId interactions may enhance or suppress Ab responses.
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Network Theory （ 1974 ）Jerne explains how the specific immune response is regulated. The immune response is regulated by a complicated network consisting of antibodies and anti-ab. The principles of the network theory are beginning to be exploited in prevention, diagnosis and treatment of disease.
Network Theory （ 1974 ）Jerne explains how the specific immune response is regulated. The immune response is regulated by a complicated network consisting of antibodies and anti-ab. The principles of the network theory are beginning to be exploited in prevention, diagnosis and treatment of disease.
Niels K. Jerne1911-1994,UK1984 Nobel Prize
Niels K. Jerne1911-1994,UK1984 Nobel Prize
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Idiotype network and antigen internal image
Ag
Ag Ab1 (Id) Ab2 (AId) Ab3 Ab
epitope
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利用独特型网络进行免疫干预的两种主要途径
Ag
Ab2
Enhance Ab1
Ab1
Ab2
B
AAb3 / Ab1
Ab1
Ab2
Ab2
Impair Ab1
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固有免疫中针对 TLR 信号转导的负向调节TIR: Toll/IL-1 receptor; ASK1: 凋亡信号调节激酶 1; IRAK: IL-1 受体相关激酶 ; MAPK: 丝裂原激活
蛋白激酶 ; MyD88: 髓样分化因子 88; NF-B: 核因子 B; PI 3K: 磷酸肌醇 3 激酶 ; PIP2 ： 2 磷酸磷脂 酰肌醇 ; PIP3: 3 磷酸磷脂酰肌醇； PKB: 蛋白激酶 B; Rac: 小 G 蛋白 ; SIGIRR: 单一 Ig IL-1R 相关分子 ;
TIRAP: TIR (Toll/IL-1 受体 ) 相关蛋白 ; TRAF6: TNF 受体相关因子 6 。
炎症细胞因子基因转录
TLR4 CD14ST2SIGIRR
MD2
MyD88
TIRAP
TRAF6
SOCS1 IRAK1IRAK4
NF-B
MAPKPKB
PI 3K
MyD88s
IRAK-M
受体衔接蛋白信号分子激酶转录因子抑制因子基因转录 激活 抑制
Rac1
PIP2 PIP3
ASK1
TIR TIR
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C
蛋白质泛素化降解
Jak
Stat
CIS
SOCS1
SOCS3
Jak
A
Jak
Stat
Stat
胞核
DNA
细胞因子受体 细胞因子
SOCS 家族部分成员 D
N 端区 SH2 结构域 SOCS 框
胞核
B
基因 X,Y,Z
SOCS 基因
生物学效应
Yp
Stat
其它信号途径
基因转录
Stat
细胞因子细胞因子受体
磷酸化
胞核
Jak
Y
CISSOCS1SOCS2SOCS3
pY
SOCS 蛋白以负向反馈环路阻抑细胞因子的信号转导
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补体对免疫应答的调节作用
补体对免疫应答的调节作用
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免疫细胞激活性受体和抑制性受体及其作用特点免疫细胞激活性受体和抑制性受体及其作用特点
基因转录
激活 抑制
Zap-70, Syk SHP-1, SHP-2
ITAM ITIM
Src PTK
PTK PTP
磷酸化
激活性受体
抑制性受体
磷酸化 脱磷酸化
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T 细胞激活及相关免疫反应中的共信号分子及其受体 家族 配体 受体 ITAM/ITIM
Ig-SF B7-1 CD28 ITAM B7-2 CTLA-4 ITIM B7-H1 PD-1 ITIM B7-DC ? B7-H2 ICOS B7-H3 ? HVEM BTLA ITIM
TNF CD40L CD40 OX40L OX40 4-1BBL 4-1BB
T
T
APC
APC
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24 h
B7
CD28
Ag
TCR
B7
CTLA-4
Activation
I T I MI TAM
inhibitionT cells
Negative regulation of T cell activation by CTLA-4
18Receptors of human NK cells
Inhibitory receptorInhibitory receptor
Activation receptor
Activation receptor
Ig super family
Ig super family
C-Lectin SF
C-Lectin SF
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allo-cell
tumorcell
normalcell
virus-Infected
cell
NK
NK
NK
NK
+ +
+ +
–
kill
kill kill
no kill
NK’s cytotoxic activity depends on activation of the signaling initiated by the ligation of inhibitory receptor with its ligand
activation receptor
inhibitory receptor
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T Cell
B cell
T cell
Mast cell
NK cell
TCR-CD3
BCR-Ig/Ig
V9V2 TCR
FcRI
KIR-S + DAP12CD94/NKG2C + DAP12
NKG2D + DAP10NCR + /FcR1CD16 + /FcR1
CTLA-4, PDL-1, BTLA
FcRII-B, CD22
CD94/NKG2A
FcRII-B
KIR-LCD94/NKG2A
ILT2
Cell Activating receptor Inhibitory receptor
Activating receptor and Inhibitory receptor of Immune cells
免疫细胞的免疫调节作用
Regulatory T Cells(Treg)
• Suppressor T cells (Ts) (1970s)
• Regulatory T lymphocytes (Treg) are a subset of CD4+ T cells whose function is to suppress immune responses and maintain self-tolerance
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Treg ： Marker
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Treg
• Humans IPEX (immune dysregulation, polyendocrinopathy,enteropathy, X-linked syndrome) is also associated with deficiency of Treg and is now known to be caused by mutations in the FOXP3 gene.
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Treg ： Generation and Maintenance
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Treg:subsets
characteristic Nature Treg adaptive Treg
Induction location Thymus (periphery), periphery
Foxp3 +++ +
IL-2 dependence + +
CD25 +++ -/+
Antigen specificity Auto-antigen Tissue-specific Ag and exogenous Ag
mechanism Cell-contact, CK independence
Cell-contact, CK dependence
Function Inhibit ART mediated Response
Inhibit pathological response
Example CD4+CD25+T CD4+ Tr1,Th3
Naturally Treg and adaptive TregNaturally Treg and adaptive Treg
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Th1,Th2,Th17
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共刺激
IFN-TNF-
CCR5CXCR3
IL-4IL-5IL-13
CCR3,4,8
Th1
Th2
IL-4
pMHC
Th 0初始 T
IL-4RStat6
IL4
Gata3
IFNG
IFN-R
IL-12IL-12R
pMHC
TCRStat4 Stat1
IFNG
T-bet
IL4
IL-23IL-23R
Stat3
IL17
IFNG, IL4
IL-17IL-17F
Th17
IL-23
IL-12
IL-4
IFN
细胞免疫
体液免疫
炎症反应
IL-17RORt
Th1,Th2,Th17
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Counter action of Th1 and Th2 subsetsCounter action of Th1 and Th2 subsets
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IFN- induced Th1 to activate intracellular killing
MacrophagesMacrophages TB in Lysosomes TB in Lysosomes
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Th2
Mast cell
Eosinophils
IgE
developing
Developed
Helminthinfection
Allergic
Th2 reaction:bad or good
Natural Selection
Population 1/3
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其他形式的免疫调节
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Regulation by apoptosis1. Activation-induced cell death (AICD)
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Regulation by neuroendocrine system
Lymphocytes express receptors for
many hormones, neurotransmitters and
neuropeptides.
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Genetic control of immune response 1.Control of immune response by MHC• Immune response genes (Ir) control all
immune responses• Most of the polymorphic residues in
MHC molecules reside in the peptide-binding groove
• MHC restriction APC-Th, Th-B MHC II CTL-Target MHC I 2. Non-MHC-linked genes affect immune
response :TCR ， BCR ， C
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Question
• The inhibitory receptors of immune system and its biological significance
• Difference between nature Treg and inducible Treg
