Chapter 14 Chapter 14

T Cell Mediated Immune ReT Cell Mediated Immune Re

sponsesponse （（ CMICMI ））

Chapter 14 Chapter 14

T Cell Mediated Immune ReT Cell Mediated Immune Re

sponsesponse （（ CMICMI ））

Contents PartⅠ General introduction PartⅡ T cells mediated immune response PartⅢ NKT cell and δT cell mediated immune responsePartⅣ Unspecific activation of T cells

Chapter 14 T Cell Mediated Immune Response （ C

MI ）

PartⅠ Introduction Conception of immune response Stages of immune response Sites of Immune response Types of immune response

Broad sense of immune response:• Unspecific immune response (innate immunity) barrier structure immunocytes: NK, Mф, DC, B1, γδT immune molecules: C, CK, lysozymes• Specific immune response (adaptive immunity) T cell mediated immune response B cell mediated immune response

1. Conception of immune response

Prevention from InfectionPrevention from Infection

1. Conception of immune response

Narrow sense of immune response:specific immune response (Adaptive immunity)

Definition: a process that ICC recognize the antigens specifically, then activate (or lose their ability to be activated), proliferate, differentiate and play immunological effect.

2. Stages of Immune response

(1) Induction stage: Ag processing, presentation and recognition.(2) Reaction stage: activation, proliferation and differentiation of ICC (dual signals, CKs).(3) Effect stage: play immunological effect (CK, CTL,

Ab).

3. Sites of Immune response----peripheral immune organs

Lymph node, Spleen, MALT

被膜

输出淋巴管

Capture and presentation of exogenous Ags

tissue tissue

Lymphatic vessel

DC

antigen

Afferent

Lymphatic vessel

cortex

Lymph node Lymph node

4. Types of adaptive immune response

• By consequence Positive Ir: Normal Ir------anti-tumor, anti-infection Abnormal Ir------hypersensitivity, autoimmunity Negative Ir: Normal Ir------self immune tolerance Abnormal Ir------tumor, infection

• By mediating cells T cell mediated immune response---CMI B cell mediated immune response---HI

PartⅡ Cellular immunity T cell mediated immune response

(CMI) CD4+T cell mediated immune

response

CD8+T cell mediated immune response

Cell surfacepeptides

of Ag

Antigens must be processed in orderto be recognised by T cells

YT

T cellresponse

No T cellresponse

No T cellresponse

No T cellresponse

No T cellresponse

Solublenative Ag

Cell surfacenative Ag

Soluble peptides

of Ag

Cell surface peptides of Ag presented by cells that express MHC molecules

ANTIGENANTIGENPROCESSINGPROCESSING

APCAPC

The process of T-cell mediated Immune response

1.T cells recognize the Ag peptide-MHC complex on APC

------MHC restriction2. Activation, proliferation and different

iation of T cells ------Dual signals3.The functions of effector T cells ------Th cell and CTL (Tc cell)

CD4+T cell mediated immune response

1. CD4+T cells recognize the Ag peptide-class Ⅱ MHC complex on APCs

------MHC restriction

(1) Exogenous antigens----APCs (2) Ag recognition: TCR on T cells bind with Ag

peptide-MHC complexes on APCs specifically.• Dual recognition: CDR1, CDR2 recognize MHC-α

helix, CDR3 recognizes Ag peptide.• MHC restriction

Three dimensional structure of TCR

Anatomical mechanism of TCR recognizes MHC/antigenic peptide

MHC-helix

Antigenic

peptide

CDR1 CDR2

CDR3 CDR3

CDR2 CDR1

TCR-chain

TCR-chain MHC-helix

CDR3 CDR2,1CDR1,2

T cell synapse• a special structure between T and APC• T cell synapse can be called

immunological synapse. When TCR complex recognizes peptides/MHC on APC, several T cell surface proteins and intracellular signaling molecules (such as CD3,CD4,CD8,CD28) are rapidly mobilized to the site of T cell-APC contact.

2. Activation, proliferation and differentiation of CD4+T cell

(1) Activation: dual signals• First signal ： specific antigen signal TCR — peptide-class Ⅱ MHC complexes CD4 — class Ⅱ MHC molecule(β2)• Second signal ： co-stimulatory signal CD28 — B7 （ CD80 、 CD86 ） CD2 （ LFA-2 ）— CD58 （ LFA-3 ） LFA-1 — ICAM-1

TCR complex

The Two-Signal Hypothesis

MHC class II

TCR CD421

T cell

APC

Co-stimulatory signal

(CD28/B7)

2. Activation, proliferation and differentiation of CD4+T cell

(1) Activation: dual signals• First signal ： specific antigen singal TCR — peptide-class Ⅱ MHC complexes CD4 — class Ⅱ MHC molecule(β2)• Second signal ： co-stimulatory signal CD28 — B7 （ CD80 、 CD86 ） CD2 （ LFA-2 ）— CD58 （ LFA-3 ） LFA-1 — ICAM-1 VLA-4 — VCAM-1

11

22

CD4

MHC-IITCR/CD3

1

ICAM-1

B7-1

B7-2

LFA-1

LFA-1

ICAM-3

LFA-3

B7-1

CD28

CD28

LFA-1

ICAM-3

CD2

2

Molecules associated with T activation

Th cell APC

CTLA-4—

APC

block Th activity

Dual signal model of Th cell activation

IL-2R

APC

Th

Signal 1

Signal 2

LPS TNF-a

IL-1

IL-6

IL-2

Th

Signal 1

Th activated

CD28

CD28B7

（ 2 ） proliferation ： CKs—IL-2• Resting T cells express low affinity IL-2R.• Activated T cells express high affinity IL-

2R and secrete CKs such as IL-2.• T cells proliferate and produce a lot of d

aughter cells under IL-2 by autocrine or paracrine.

Tm

Effector T

Proliferation of T cell

（ 3 ） Differentiation ：• Daughter cells differentiate into effector T cells

and some differentiate into memory T cells (basis of vaccine).

Th1(IL-2 、 IFN-γ 、 TNF-β ）• Thp Th0 Th2 （ IL-4 、 5 、 6 、 10 、 13 ）

IL-12

IL- 4

Ag

IL-23

（ IL-6 ， TGF-β ） Th17 （ IL-17 ）

characteristic of memory T Cells (Tm):

• Long lived cells

• CD45RA-,CD45RO+

• Easily triggered by low antigen

• Less dependent on co-stimulatory molecules

• Sensitive to CKs

• Responsible for maintaining immunological memory

Days after immunity

Rat

io o

f sp

ecifi

c T

cel

ls in

blo

od

感应阶段

Primary immunity

Secondary immunity

1/10

000

1/10

001/

100

0 7 14 21 28 35 42

Principle of T cell mediated immune response

Immunological memory

3. The functions of effector Th cells

3. The functions of effector Th cells

Th1 Th2Th1 Th2

CKsCKs

IL-2 ++++ —IL-2 ++++ —

IL-4 — ++++IL-4 — ++++

IL-5 — ++++IL-5 — ++++

IL-10 — +++IL-10 — +++

IFN-IFN- ++++ — ++++ —

TNF-TNF- +++ — +++ —

CKs for proliferationCKs for proliferation IL-2 IL-2/IL-4 IL-2 IL-2/IL-4

HelpingHelping IgG,DTH IgE/IgA IgG,DTH IgE/IgA

InhibitionInhibition Th2 Th1 Th2 Th1

（ Th1 ， Tc ）

(1) The functions of Th1 cells

Th1 cells release IFN- to activate macrophage, mediate inflammatory reaction and inhibit the function of Th2 cells.

Th1 cells release IL-2 to promote the proliferation, differentiation of Th1 cells and Tc cells.

Effect of macrophage:• Phagosize and kill pathogens• Promote Th1 activation• Mediate delayed hypersensitivity

(2) The functions of Th2 cells

Th2 cells release IL-4,5,6,10 to activate the B cells to produce Ab.

Th2 cells release IL-4,5 to promote the differentiation and development of eosinophil and mast cell.

Th2 cells release IL-10 to inhibit the activation of macrophage and function of Th1 cells.

CD8+T cell mediated immune response

1.CD8+T cells recognize Ag peptide-class ⅠMHC complex on

APC-------MHC restriction

(1) Endogenous antigens----APCs (2) Ag recognition: TCR on T cells bind wit

h Ag peptide-classⅠMHC complexes on APCs specifically.

• Dual recognition: CDR1, CDR2 recognize MHC-αhelix, CDR3 recognizes Ag peptide.

• MHC restriction

2m

TCR- chainTCR- chain

Homocysteine

HLA-A68

Peptide

Interaction between TCR and homocysteine presented by HLA-A68

C

2. CD8+T cell Activation, proliferation

and differentiation

(1) Activation: dual signal• First signal ： specific antigen signal TCR — peptide-class Ⅰ MHC CD8 — class Ⅰ MHC• Second signal ： co-stimulatory signal ？ CD28 — B7 （ CD80,CD86 ） CD2 （ LFA-2 ）— CD58 （ LFA-3 ） LFA-1 — ICAM-1

Signal 1Signal 1

Signal Signal 2 ?2 ?

APC

block block activityactivity

Dual signal model of Tc activation

IL-2IL-2

Target cellTarget cell

activate, activate, expansionexpansion

ThTh TcTcAPC APC

TcTcTumor cell

tumortumor

DC

CD28

CD28 B7B7 CD28

Activation of CD8+T cell

Virus infected DCs activate CD8+T cell directly

Help of CD4+Th cell to CD8+T cell: • Secreted IL-2 acts as the second signal • Enhance expression of co-stimulator on APC

（ 2 ） Activated Tc cells proliferate and produce a lot of daughter cells under IL-2.

（ 3 ） Daughter cells differentiate into effect

or CTL and some differentiate into memory Tc cells(basis of vaccine).

3 ． Function of effector CTLsCTLp recognized peptide-class Ⅰ MHC pr

oliferate and differentiate to effector CTL under action of IL-2 released by Th1.

The effector CTLs specifically recognize and bind Ag on target cells.

CTL releases perforin, granzymes and express Fas ligand to kill target cells.

（ 1 ） The process of CTL killing target cells

• Specific recognition and binding of target cell by CTL

• Lethal hit to target cell • Lysis or apoptosis of target cell

①

②

③

（ 2 ） Characteristics of CTL killing target cells ：

• Specific killing• ClassⅠMHC molecule restriction• Continuous killing of target cells in short ti

me, and no injury of CTL

Normal cell

No injury

No injury

（ 3） Mechanism of CTL killing target cell:

• Perforin -- osmotic lysis• Granzyme and Fas/FasL -- apoptosis• Secreted TNF and IFN- induce target cells to die

*Fas ： Apo-1 or CD95

Cell deathCell death TNF and IFN-TNF and IFN- (minor (minor pathway)pathway)

CTL cell

Target cell

Biological effect of CMI

1. Play an important role in defense agaist intracellular microbe infection.

2. Kill tumor cells or virus-infected cells. 3. Participate in graft rejection and graft-

versus-host disease(GVHD).4. Mediate type Ⅳ hypersensitivity.

Part Ⅲ NKT cell and δT cell mediated immune response

1. Ir mediated by NKT cell• NKT cell: T cell which express

molecules of NK cells• Recognize lipid Ag presented by

CD1 molecule• Activated NKT cells secrete IFN-

and IL-4

NKTcells

2. Ir mediated by T cell• CD4- and CD8- T cell• Antigens: bacteria, virus• Not need APC • No MHC restriction

PartⅣ Unspecific activation of T cells

• Superantigen• Unspecific activation• Need APC, but not processing and presentin

g• Secrete CK

Superantigen(sAg) TCRV

Antigenic peptide

Class II MHC chain

T cell

APC

The mechanism of superantigen activating T cell

Ag and SAgAntigen Superantigen

The other activators of T cells

mitogen(PHA, ConA)anti-CD3, anti-TCRαβ, anti-TCRγδ anti-CD28