Transcript Chapter14 T cell med..

Chapter 14
T
Cell Mediated Immune
Response（CMI）
T
Cell
Chapter 14
Mediated Immune Response（CMI）
Contents
 PartⅠ General introduction
 PartⅡ T cells mediated immune response
 PartⅢ NKT cell and δT cell mediated
immune response
PartⅣ Unspecific activation of T cells
PartⅠ Introduction
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


Conception of immune response
Stages of immune response
Sites of Immune response
Types of immune response
1. Conception 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
Prevention 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
Capture and presentation of exogenous Ags
tissue
DC
antigen
被膜
Lymphatic
vessel
Lymph node
Afferent
输出淋巴管
Lymphatic
vessel
cortex
4. Types of adaptive immune
response
• By consequence
Positive Ir:
autoimmunity
Negative Ir:
Normal Ir------anti-tumor, anti-infection
Abnormal Ir------hypersensitivity,
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
Antigens must be processed in order
to be recognised by T cells
T
Y
Soluble
native Ag
Cell surface
native Ag
Soluble
peptides
of Ag
APC
No T cell
response
No T cell
response
Cell surface peptides of
Ag presented by cells that
express MHC molecules
Cell surface
peptides
of Ag
ANTIGEN
PROCESSING
No T cell
response
No T cell
response
T cell
response
The process of T-cell mediated
Immune response
1.T cells recognize the Ag peptideMHC complex on APC
------MHC
restriction
2. Activation, proliferation and
differentiation of T cells
------Dual signals
3.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-αhelix, CDR3 recognizes Ag peptide.
• MHC restriction
Three dimensional
structure of TCR
Anatomical mechanism of
TCR recognizes MHC/antigenic peptide
TCR-b chain
CDR1
CDR2
CDR3
CDR3
MHC-a helix
Antigenic
peptide
CDR2
CDR1
TCR-a chain
MHC-a helix
CDR1,2
CDR3
CDR2,1
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
T cell
TCR
1
MHC class II
CD4
APC
Co-stimulatory signal
2
(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
2
1
Molecules associated with T activation
Th cell
APC
CD4
TCR/CD3
MHC-II
1
2
LFA-1
ICAM-1
CD28
B7-1
CD28
B7-2
LFA-1
ICAM-3
ICAM-3
LFA-1
CD2
LFA-3
CTLA-4
—
B7-1
Dual signal model of Th cell activation
IL-2R
Th
APC
block Th
activity
CD28
LPS
TNF-a
IL-1
IL-6
IL-2
Th
APC
B7 CD28
Th
activated
（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 daughter cells under IL-2 by
autocrine or paracrine.
Proliferation of T cell
Tm
Effector T
（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）
IL-12
Ag
• Thp
Th0
IL- 4
Th2（IL-4、5、6、10、13）
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
Immunological memory
1/1000
1/100
T cell mediated immune response
Primary
immunity
Secondary
immunity
1/10000
Ratio of specific T cells in blood
Principle of
感应阶段
0
7
14
21
28
35
Days after immunity
42
3. The functions of effector Th
cells
3. The functions of effector Th
cells
Th1
Th2
IL-2
++++
—
IL-4
—
++++
IL-5
—
++++
IL-10
—
+++
IFN-
++++
—
TNF-b
+++
—
CKs
CKs for proliferation
Helping
Inhibition
IL-2
IgG,DTH
Th2
IL-2/IL-4
IgE/IgA
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 peptideclass ⅠMHC complex on APC
-------MHC restriction
(1) Endogenous antigens----APCs
(2) Ag recognition: TCR on T cells bind
with Ag peptide-classⅠMHC complexes
on APCs specifically.
• Dual recognition: CDR1, CDR2 recognize
MHC-αhelix, CDR3 recognizes Ag peptide.
• MHC restriction
Interaction between TCR and homocysteine
presented by HLA-A68
TCR-a chain
TCR-b chain
Homocysteine
C
Peptide
HLA-A68
b2m
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
APC
Signal 1
Signal 2 ?
Dual signal model of Tc activation
tumor
Tc
Target
Tumorcell
cell
block
activity
CD28
DC
Tc
APC
Th
B7
CD28
B7
CD28
IL-2
activate,
expansion
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
effector CTL and some differentiate into
memory Tc cells(basis of vaccine).
3．Function of effector CTLs
CTLp recognized peptide-class Ⅰ MHC
proliferate 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 time, and no injury of CTL
No injury
Normal cell
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 death
TNF and IFN-
(minor 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: abT 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
presenting
• Secrete CK
T cell
The mechanism of
superantigen
activating T cell
TCRVb
Superantigen(sAg)
Antigenic peptide
Class II MHC a chain
APC
Ag and SAg
Antigen
Superantigen
The other activators of T cells
mitogen(PHA, ConA)
anti-CD3, anti-TCRαβ, anti-TCRγδ
anti-CD28