11

ImmunoregulationImmunoregulation

22

The immune response is subject to a variety of control mechanisms which serve to restore the immune system to a resting state when the response to a given antigen is no long required.

33

抗体浓度对抗体产生的调节家兔经抗原免疫后产生特异性抗体，用血清交换人为降低抗体浓度后，可引起抗体产生量的反馈性升高 , 并在到达一定强度后逐渐下降。说明机体可感知自身抗体浓度的变化，并

自行启动调节机制

44

Immunoregulation:homostasisImmunoregulation:homostasis

• Normal

anti-infection

anti-tumour

• Abnormal

Auto-immune disease

Tumour

Persisitent infection

Allergy

55

Regulation of innate immunityImmunoregulation mediated by Inhibitory ReceptorRegulation by TregIdiotype networkImmunoregulation by other mechanism

ImmunoregulationImmunoregulation

66

A. Regulation of innate immunity1.Feedback Regulation of secretion of inflammatory factor

7

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

88

A. Regulation of innate immunity1.Regulation by SOCS (suppressor of cytokine signaling)

9

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

10

11

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

12

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

13

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

14

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

1515Receptors of human NK cells

Inhibitory receptorInhibitory receptor

Activation receptor

Activation receptor

Ig super family

Ig super family

C-Lectin SF

C-Lectin SF

16

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

17

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

C. Regulation 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

18

Treg ： Marker

19

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.

20

TregTreg ：： Generation and Generation and Maintenance Maintenance

2121

2222

Treg:subsetsTreg: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

2323

2424

2525

26

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-17

RORt

2727

Counter action of Th1 and Th2 subsetsCounter action of Th1 and Th2 subsets

2828

2929

30

IFN- induced Th1 to activate intracellular killing

MacrophagesMacrophages TB in Lysosomes TB in Lysosomes

31

Th2

Mast cell

Eosinophils

IgE

developing

Developed

Helminthinfection

Allergic

Th2 reaction:bad or good

Natural Selection

Population 1/3

3232

D. 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.

3333

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

3434

3535

36

Idiotype network and antigen internal image

Ag

Ag Ab1 (Id) Ab2 (AId) Ab3 Ab

epitope

37

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

3838

E. Regulation by apoptosisE. Regulation by apoptosis1. Activation-induced cell death (AICD)

4040

F. Regulation by neuroendocrine F. Regulation by neuroendocrine system system Lymphocytes express receptors for

many hormones, neurotransmitters and

neuropeptides.

4141

4242

4343

G. 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

4444

QuestionQuestion

• The inhibitory receptors of immune The inhibitory receptors of immune system and its biological significancesystem and its biological significance

• Difference between nature Treg and Difference between nature Treg and inducible Treginducible Treg