Immune response and regulation

免疫应答 (immune response, Ir)

Body receive stimulation from Ag ， Specific lymphocytes recognize Ag ， they activate, proliferate and differentiate or become a state of anergy and apoptosis ， exert biological effect.

Immunological functions

Functions Normal abnormal

Defense clear pathogen ↑hypersensitivity 、 (anti-infection ）↓ immune deficiency （ chronic infection ）

homeostasis tolerant to auto-tissue ↑Autoimmune disease （ clear damaged and aged cells ）

surveillance clear mutate cell ↓ ontogenesis （ Anti-tumor ） (persistent viral infection )

Classification

•Innate immunity （ non-specific ）

•Acquired immunity （ specific ）

- Humoral immunity

- Cellular immunity

• Physiological IR （ Immune protection ） Non-self reject Self tolerant

• Pathological IR （ Immune damage ） IR too high hypersensitivity IR too weak Immune defectTolerance terminate Autoimmune disease

Classification

Classification of specific immunity

（一）体液免疫（ humoral immunity ）–To exogenous Ag or soluble Ag outside of cell

（二）细胞免疫 (cell-mediated immunity)

–To endogenous pathogen ， cellular Ag（ tumor Ag 、 grafted Ag ） .

Place of Ir

Peripheral immune organ (lymph node 、spleen and so on).

Process of Ir

3 stages ：Presenting and recognizing Ag ：Activation 、 proliferation and differentiation

Effect

Basic process of Ir

Cellular immune response

T recognize Ag and activation

Effect of T cell mediated IR and

mechanism

Biological effect of cellular immunity

3 stages ：

③Production of effector cells

①Recognition phase

②Activation ， proliferation ， differentiation

APC presenting Ag to T cell

Ag +APC peptide-MH Complex T cell

Interaction between APC and T cell

• TCR peptide-MHC

• LFA-1 change conformational structure

• CD4 MHC

CD8 MHC

• Co-stimulatory molecule

一、 Requirement for T recognizing Ag and activation

（一） T cell recognize Ag* MHC restriction

TCRαβchainrecognize

Peptide on APC (Epitope of T cell )

MHC on APC surface (MHC restriction)

TCR 的 MHC 限制性识别示意图

Molecules involved in T cell recognition

Recognition phase

1. Take in Ag ：

2. Process and present Ag:

3. Interaction between APC and T cell• Recognition of Ag ： Double recognition: TCR-peptide ， TCR-MHC Co-receptor:CD4-MHCII, CD8-MHCI• Binding of co-stimulatory molecules on APC and T cells ： B7-CD28

Depend on

2 signals and CK

第二节 Activation ， proliferation ，differentiation

第二节 Activation ， proliferation ，differentiation

T cell activation for signal requirement

1 、 2 signals for Th activation （ 1 ） Active signal 1 (Ag)

TCR specifically recognize peptide/MHC

（ 2 ） Active signal 2 (binding of co-stimulatory molecule)

B7-CD28 Adhesion molecules-their ligands

2 、 CK(IL-2 、 4、 12…)

Signal 1 （ Ag ）： TCR recognize peptide-MHC Signal 2 （ Co-stimulator ）： binding of ADs

CD4+T activationT cell activate signal 1 （ Ag recognition signal ）

T cell activate signal 2 （ co-stimulator signal ）

Flash

* T acquire signal ， but lack signal 2 ， anergy and apoptosis occur.

* Block or enhance active signal

2, can reduce or increase Ir 。

The first signal for T cell activation

TCR MHC-peptide

Specifically recognize

Second signal for T cell activation

AD on APC + co-stimulatory signal

AD on T cell

CD28/B7 ： involve in T cell activationCTLA4/B7 ： suppress T cell activation

CK ： Promote T cell activation

Proliferation and differentiation of T cell

Th effector T

CTL•Active T memory T

2. Proliferation and differentiation of CD4+T

Active T

Express variety of CKs and receptors

T cell grow

Th0

Th1 Th2

IL-12,IFN- IL-4

IL-2+IL-2R

Th divide into Th1 and Th2

Proliferation and differentiation of CD8+T

•Th independent （ direct activation ） •Th independent （ indirect activation ）

IL-2

IL-2

IL-2

• go to effector T ；

• go to memory T ；

• go to apoptosis.

Where will Active T go?

二、 Effect and mechanism of T cell mediated IR

( 一 ) CD4+Th1 mediate effect (inflammation)

( 二 ) CD8+TC mediate effect (lyses of cell)

Cytotoxicity of CD8+CTL(TC)

MHC restriction recognition of Tc* TCR recognize peptide/MHC-I on target cell;

requirement for Tc activation Active signal 1: TCR recognize Ag;

Active signal 2: Co-stimulatory molecule bind its ligand

CK: APC→ active Th

→CKs （ IL-2 ， IL-6… ）

A ： lack active signal 1 ， TC leave target cell

B ： TC recognize infected cell ， With signal 1 and 2 ，TC grow ， kill target cell and leave

A BDouble signals for TC activation

The killing mechanism for Tc cell

• The specific recognizing and binding phase

• The killing phase （ 1 ） active CTL de-granule release perforin →lysis of target cells release granzyme→ apoptosis of target cells

（ 2 ） Fas-FasL pathway → apoptosis of target cells

（ 3 ） Release cytotoxic CKs （ IFN-γ ， TNFα/β ）

CTL release perforin and granzyme to cause necrosis and apoptosis of target cell

CTL release perforin and form a channel in target cell membrene

（ G=T 细胞颗粒， Go= 高尔基体， M= 线粒体， N=核）

TC express FasL to induce apoptosis of target cell

Actuve TC express FasL AAAAAA

Interaction of Fas-FasL to induce apoptosis of target cell

FasL

Viral infected targeted cell

CTL killing possess high Ag-specificity and MHC re

striction

CTL kill one more target cells

Property ：Specificity 、 MHC restriction 、 high efficacy

CD8+TC mediated Ir T/Target cell

TCR recognize

peptide-MHC-I Interaction of ADs

CD4+Th activate

Secret CKs

Resting Tc transform to active Tc

Release perforin and granzyme Fas 、 FasL

Death of target cell

signal

signal

21

The effect caused by CD4+Th1

Release many kinds of lymphokines ， lead to inflammation

1 、 Function on M —secret CK–Activate M :IFN-γ 、 CD40L

–Induce and attract M: IL-3 、 GM-CSF 、 TNF 、 MCP-1

迟发型超敏反应 (delayed type hypersensitivity, DTH) ： caused by lymphocytes 、 lymphocytes and monocytes are main cells found in inflammation site.

Activation 、 proliferation 、 differe

ntiation and migration of immune cells take too long time, inflammation occur too late and maintain longer, referred to DTH.

Active M activated by Th1

Gathering of lymphocytes and monocytes/M

2 、 to T cells promote proliferation of Th1 、CTL ， enlarge immune effect

3 、 to B cells promote the production of Ab4 、 To neutrophill activate

CD4+TDTH mediated cellular IrTDAg

APC take in 、 process 、 present Ag

Active signal 1

CD4+Th1 recognize peptide-MHC-II complex Th1 activation

proliferation

Active signal 2

Th1 contact APC

CKs

Activated MResting M Secret inflammatory Cks

DTH

CKs

Effect of active T

( 一 ) CD8+CTL mediate cytotoxicity

( 二 ) CD4+Th1 mediate DTH

( 三 )CD4+Th2 assist B to produce Ab

The process of Immune responseThe process of Immune response

三、 Biological effect of cellular immunity

( 一 ) Killing endogenous microorganism → anti-

infection immunity;

( 二 ) Killing tumor cell → anti-tumor immunity;

( 三 ) Immune damage

killing grafted cells → graft rejection reaction

killing auto cells and tissue → AID 。

DTH

Review Questions

• Describe the process of IR mediated by CD8+T. 简述 CD8+T 细胞介导的免疫应答过程。

• Describe the process of CD4+T activation 简述 CD4+T 细胞的活化过程。

• Describe the interaction of APC and Th 简述 APC-Th 细胞是如何相互作用的。