Naïve T cells
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Transcript of Naïve T cells
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Naïve T cells effector T cells
Target cells
APC
effector T cells
Ag
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1. Survival signals: re-enforce the positive selection
by MHC: self peptide
2. Ensure the high probability of encountering pathogens, Only one in 104-106 is to be specific for particular Ag
Naïve T cells circulate from bloodstream through lymphoid organs and back to bloodstream, making contact with many thousand APC in lymphoid tissue:
Naive T cells encounter antigen during their Recirculation through peripheral lymphoid organs
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Activation of naïve T cells required three signals delivered from APC
CD28-B7 induce T cells express growth factor IL-2 and its high affinity receptor (CD25, IL2R)
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2. The production of armed effector T cells
3. General properties of armed effctor T ells.
4. T ell mediated cytotoxicity
5. Macrophage activation by armed CD4 Th1 cells
T cell activation and Cell Mediated Effector Response
1.Entry of naïve T cells and APC cells into peripheral Lymphoid organs
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1. Lymphocytes entyry into lymphoid tissues
3. Antigen presentation cells
-------Adhesion molecules
Entry of naïve T cells and APC cells into peripheral Lymphoid organs
-------Chemokines
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Distinct stages for lymphocytes entry into lymph node require the activity of adhesion and chemokines
CCL21:CCR7 (T cells) CXCL12:CXCR4 (Tcells)
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Lymphocyte migration, activation, and effector function depend on cell-cell interaction mediated by cell
adhesion molecules
Adhesion molecules:1.Selectin, integrin, members of Ig superfamily, mucin like molecules2.Broad role in generation of lymphocyte response3.migration, effector T cells-target cells, getting lymphocyte together; B-T cell interaction
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Selectin: lymphocyte homing to particular tissue leukocyte: L selectin (blood to lymph tissue), vascular endothelium : P-or E- selectin (blood to infection sites)
Cell surface sugar group : Vascular addressins: CD34, GlyCAM-1
Sulfated Sialyl-LewisX
L-Selectin and mucin like vascular addressins
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Integrins are important in T-lymphocyte adhesion
, subfamily (large , common ), 2, leukocyte integrins, all T cells, known as LFA -1(lymphocyte function associated antigen-1) , most important one, naïve and effector T cell migration1, leukocyte integrins, late stage in T cell activation, very late activation antigen (VLA), armed effector T cell to infection sites
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Integrins are important in T-lymphocyte adhesion
Integrins: (development, inflammatory response)
1.cell-cell, cell-extracellular matrix; signals induce intergrin bind to their ligand tightly:
a. chemokine enhance integrin binding to its ligand ex: CCL21 (SLC; secondary lymphoid tissue chemokines) expressed by DC, stromal cells, high vascular endothelium cells, bind to CCR7, (naïve T cell to lymphoid tissue)
b. T cell receptor trigger T cell integrin-ligand tightly
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Ig domain Adhesion molecules involved in leukocyte interactions
Ig domain superfamily:
CD4, CD8, CD19, intercellular adhesion molecules (ICAM)
ICAM-1.2.3 ICAM1,2: endothelium cells, lymphocytes, ICAM3: naive T cells
LFA: lymphocyte function association antigen
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Lymphocytes in the blood enter lymphoid tissue by crossing the walls of high endothelium venules
CCL21
血球滲出
CCL21CCL18
CCR7
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1. Lymphocytes entry into lymphoid tissues
2. Antigen presentation cells
-------Adhesion molecules
Entry of naïve T cells and APC cells into peripheral Lymphoid organs
-------Chemokines
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Antigen presenting cells
Dendritic cells vs Macrophage vs B cells
Selectivity of antigen uptakeAntigen process prosperities, costimulatory molecules, Migration behavior
Distinct function of APC in initiating T cell response
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Antigen-presenting cells are distributed differentially in the lymph node
Dendrtic cells: T cell area a wide variety pathogensMacrophage: Marginal sinus, (lymph afferent), medullary cord (Lymph efferent) T cell areas ingested pathogens
B cells: lymphoid follicles soluble antigens (toxin)
B cells as APC require:1. Appropriate receptor (internalize)2. Antigen at high density
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Two different functional classes of dendritic cells
cDC pDC
cDC: CD11c+: activation of naive T cells
pDC: sentinels 哨兵 primarily for virus infection and produce a lot of IFN and less efficiency in priming naïve T cells, TLR7 and TLR9 for sensing virus infection
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Dendritic cells process pathogens via different routes
DC are susceptible to infection by quite a number of viruses
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Dendritic cells mature through at least two definable stages to become potent antigen-presenting cells
in lymphoid tissue
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1. The ability to activate T cells Lymphoid>>>epithelial and solid organs
2. Immature dendritic cells: Low MHC, No B7 phogocytosis: using DEC250 receptor Macropinocytosis (non-specific) Induce tolerance to self antigen
3. Mature dendritic cells: High level: MHC, adhesion adhesion molecules, DC-SIGN, chemokine (DC-CK CCL18, attract naïve T cells),CCR7 (chemokine receptor, homing to lymphoid org.), IL-12
Dendritic cells mature through at least two definable stages to become potent antigen-presenting cells
in lymphoid tissue
Inflammatory response: ----transport antigen to the local lymphoid tissue---- Enable APC to present antigen effectively to naïve T cells.
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Microbial substances can induce co-stimulatory activity in macrophages
Kupper cells and Macrophage in spleen :little MHC II and No TLR
Resting macrophage:Little or no MHCIINO B7
Insoluble antigen
Macrophage are scanvenger cells that can be induced by pathogens to present foreign antigens to naïve T cells
Adjuvant
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B cells can use their immunoglobulin receptor to enhance the presentation of specific antigen very efficiently to T cells
B cells are highly efficient at presenting antigen that bind to their surface immunoglobulin
B cells: soluble antigen, constitutively high levels of MHC II, induced B 7.2 by microbial Protein
How important of B cells as APCs? vs Dendritic cellsSoluble antigens are not abundant during natural infection
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Summary of APC
The properties of the various antigen-presenting cells
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2. The production of armed effector T cells (Priming)
3. General properties of armed effector T ells.
4. T ell mediated cytotoxicity
5. Macrophage activation by armed CD4 Th1 cells
T cell activation and Cell Mediated Effector Response
1.Entry of naïve T cells and APC cells into peripheral Lymphoid organs
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Cell-surface molecules of the Ig superfamily are important in the interactions of lymphocytes with
antigen-presenting cells
DC-sign: lectin only dendritic cells
CD58: also known as LFA-3
The initial interaction of T cells with APC is mediated by cell-adhesion molecules
ICAM3: LFA1 and DC-Sign
Synergize
redundancy
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Transient adhesive interactions between T cells and antigen-presenting cells are stabilized by specific antigen recognition
The initial interaction of T cells with antigen-presenting cells is mediated by cell adhesion molecules
TCR+MHC-peptide: Increase the affinity of ICAM1 and LFA1The association lasts for several days , during which time naïve T cell proliferates and its progeny associate with APC: proliferation and differentiation to armed T cells
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Activation of naïve T cells required three signals delivered from APC
CD28-B7 induce T cells express growth factor IL-2 and its high affinity receptor (CD25, IL2R)
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The principal co-stimulatory molecules expressed on antigen-presenting cells are B7 molecules, which bind the T-cell protein CD28
Co-stimulatory molecules
B7 moleculesB7.1 (CD80) and B7,2 (CD86)Ig superfamily
CD28: ligand of B7
CD28-B7 +TCR-Self/MHC
CD40L (T cell surface)
CD40L-CD40 (APC)
B7 (APC) Another costimulation molecules: T cells: 4-1BB (CD137)APC: 4-1BBL
IL-2 and IL-2R increase
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High-affinity IL-2 receptors are three-chain structures that are produced only on activated T cells
Activated T cells synthesize the T cell growth factor interleukin-2 and its receptor
CD25: chain
Resting T cells: , moderate affinity high IL-2Activated T cells: High affinity Low IL-2
IL-2 are necessary for the T cell proliferation
Anergic cells can not produce IL-2
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Activated T cells secreted and response to IL-2
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T-cell activation leads to the increased expression of CTLA-4, an inhibitory receptor for B7 molecules
CTLA-/-: proliferative massively, Lymphadenopathy, is important in lymphocyte homeostasis
CD28: rest and activated T cells
CTLA-4 (CD152)--CD28 related protein also bind to B7--Expressed on activated T cells. --less than CD28 even in high peak, --In terms of the B7 avidity, CTLA is 20X higher than CD28
B7-CD28: positive signalsB7-CTLA4: inhibitory signals
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The requirement for one cell to deliver both the antigen-specific signal and the co-stimulatory signal is crucial in preventing immune responses to self antigens
T cell anergy
MHC class I present endogenous peptide whichis not eliminated in the thymus
Why the retention of angeric T cells?
Anergic cells can not produce IL-2
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Armed effectors T cells can respond to their target cells without co- stimulation
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Armed effector T cells changes the expression of several cell-surface molecules
Armed effector : Loss of L-selectin results in ceasing to recirculate through lymph node Expression of VLA-4 allow the activated cells to bind to VCAM which is expressed at the sites of inflammation
CD45RO: associate with TCR and CD4, more sensitive to peptide/MHC
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1.Naive CD8 T cells can be activated directly by potent antigen-presenting cells
Naïve CD8 T cells can be activated in different ways to become armed effector cells
Need more co-stimulatory molecules than ThTc against Tumor
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Some CD8 T-cell responses require CD4 T cells
CD40-CD40L:Increase the co-stimulatory molecules on APC
4-1BBL:another co-stimulatory molecules only expressed on activated DC, macrophage and B cells
Activated CD40 increase the co-stimulatory molecules expressed on APC
2. Naïve CD8 T cells can be activated in the presence of Th. In these response CD8 and CD4 T cells must recognize related antigens on the surface of the same antigen presentation cells
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Various signal3 causes naïve CD4 T cells to acquire distinct effector function
Nature T reg: CD4+CD25+, 10-15% Inhibit T cell proliferation, IL10 and TGF
Th3: Mucosa, IL-4, IL-10 and TGF Tr1: culture in IL-10, TGFAdaptive regulatory: TGFinducted Foxp3, TGF
IL23
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The different type of effector cells are specialized to deal with different types of pathogens
Effectors Action depend on:The array of membrane, secreted protein, and mediator released upon receptor ligation
The effector proteins focus on the target cell by mechanism that activated by recognition of antigen on the target cells
Chemokines
Prevent autoimmunity
proinflammatory
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2. The production of armed effector T cells
3. General properties of armed effctor T ells.
4. T ell mediated cytotoxicity
5. Macrophage activation by armed CD4 Th1 cells
T cell activation and Cell Mediated Effector Response
1.Entry of naïve T cells and APC cells into peripheral Lymphoid organs
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Interactions of T cells with their targets initially involve nonspecific adhesion molecules
TCR+MHC-peptide;prolong the binding of target cells with effector cells
Th bind to macrophage or B cells for long period
? Disengage from target cells.
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Tight junctions are formed between armed effector T cells and their targets
SMAC: supramolecular adhesion complex
The area of contact between an armed effector T cells and its contact forms an immunological synapse
a B cell: a T cellpSMAC cSMAC
Control the delivery of effectors:1.Stable binding, tight held, narrow space2.Focus the delivery at the site of contact 3. Triggers the synthesis or release
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The polarization of T cells during specific antigen recognition allows effector molecules to be focused
on the antigen-bearing target cell
Nonspecific adhesion binding
TCR binding to target cells
T cell become polarized : aligns the microtubule organization center (MTOC), sectory aparatus, Golgi
Binding of the T-cell receptor complex direct release of effector molecules and focus them on the target cells
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The different types of effector T cells produce distinct sets of effector molecules
Fas ligand (FasL): Membrane associated TNF-related moleculesexpressed by cytotoxic T cells and some Th cells,which kill the activated Fas bearing lymphocytes
The effector functions of T cells are determined by the array of effector molecules that they produce
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The nomenclature and functions of well-define T-cell cytokines I
Most of the cytokines have local effects that syngergize with those of the membrane bound effector molecules
Synthesis of IL-2,IL-4 and IFN- is controlled and confined to target cells
More distant effect:IL-13 and GM-CSF producing macrophage and granulocytes
IL-5: eosinpophilIL-3 and GM-CSF: DC
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The nomenclature and functions of well-defined T-cell cytokines II
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The nomenclature and functions of well-defined T-cell cytokines III
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Cytokine-mediated generation and cross regulation of Th subsets
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Cytokine receptors belong to families of receptor proteins, each with a distinctive structure
Cytokines and their receptors can be grouped into a small number of structural families
I:: ligand specificity or : signal transduction
TNF receptor: ligand: trimer, membrae bound
Cytokines: Hematopoietin IFNTNF
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2. The production of armed effector T cells
3. General properties of armed effctor T ells.
4. T ell mediated cytotoxicity
5. Macrophage activation by armed CD4 Th1 cells
T cell activation and Cell Mediated Effector Response
1.Entry of naïve T cells and APC cells into peripheral Lymphoid organs
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Cytotoxic CD8 T cells can induce apoptosis in target cells
Why cell mediated cytotoxicity ? Intracellular pathogen:Not accessible to AbEliminated by destruction or modification of infected cells
Tc+target cells:Program to death within 5 minutesDeath take hours to be evident ???
Apoptosis:Kill host cell , cytosolic pathogens Nonviral cytosolic pathWhy is apoptosis but not necrosis ????
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Cytotoxic effector proteins released by cytotoxic T cells
Ca2+ dependent release of specialized lytic granule
Perforin: pore
Granzymes:Three digestive enzymeSerine protease (as trypsin and chymotrypsin)
Granulysin :Apoptosis and antimicrobial
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CTL-mediated pore formation in target-cell membrane
Perforin+ phosphorylcholine Polymerize pore+Ca2+
G:granules, N: nucleus, M: mitochondrion, Go: Golgi.
Perforin released from the lytic granules of cytotoxic T cells can insert into the target cell membrane to form pores
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Capase 3
Capase-activated deoxyribonucleotides (CAD)
Apoptotic cells was taken up by phagocytosis and completely digested without induction of co-stimulatory protein
CAD I-CAD
CAD
TCR aggregation signal through the ITAM motif for granule release, similar to mast cells
Both Perforin and granzyme are required for the effectively cell killing
Two pathways of target-cell apoptosis stimulatedby CTLs
Granzyme B
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Cytotoxic T cells kill target cells bearing specific antigen while sparing neighboring uninfected cells
1. Store the inactivated cytotoxic proteins in lytic granules
2. TCR aggregation leads to synthesis of perforin and granzyme
3. Kill the target cell one by one, one point contact at any one time
4. Tc produce IFN-inhibit viral replication)TNFTNFkill some target cells).
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2. The production of armed effector T cells
3. General properties of armed effctor T ells.
4. T ell mediated cytotoxicity
5. Macrophage activation by armed CD4 Th1 cells
T cell activation and Cell Mediated Effector Response
1.Entry of naïve T cells and APC cells into peripheral Lymphoid organs
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TH1 cells activate macrophages to become highly microbicidal
--Clinical important infections, microbial inhibit the fusion of phagosome and lysosome or acidification of these vesicles --Macrophage require two signals to be activated:1. IFN-and other ways sensitizing cells to IFN , such as CD40L, 2. Membrane associated TNF-, TNF- of macrophage can replace CD403. Tc produce IFN- (cooperate with little LPS) IFN-: Th1 and Tc, but not Th2
The production of cytokines and membrane-associated molecules by armed CD4 Th1 cells requires new RNA and protein synthesis
Th1 contact with target cells longer than Tc:
--In many cases the macrophage is able to destroy pathogens without the need for T cells activation
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Activated macrophages undergo changes that greatly increase their antimicrobial effectiveness and amplify
the immune response IFN-: contact and focal secretionActivated MF: 1. more effectively fuse phagosome and lysosome 2. MHC II, B7, CD40 and mTNF-
4. TNF-(M) +IFN- (Th1)iNOS, NO, O2
- (destroy extracellular Pathogens)
IL-12Naïve T cells
Th1
5. Bad: Consume large energy, tissue destruction
6. regulation: IFN-: mRNA half life is short, new protein promote cytokine mRNA degradation TGF-, IL-10 (Th2), (Th2) inhibit M activation
3.
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The immune response to intracellular bacteria is coordinated by activated TH1 cells
CCL2
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Granulomas form when an intracellular pathogen or its constituents cannot be totally eliminated
T cells: Th1 and Th2, Th2 preventing wide spread tissue damage by regulating Th1 activatity.
Lack of oxygen and cytotoxic effect of activated macrophage cause the dead center like cheese: Caseation necrosis
Th1, nonactivation, disseminated infection, present in patients with AIDS and concomitant mycobacterial infection
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Further Reading:Immunology (Kuby): 259-260, 262-265, 351-361Immunobiology(Janeway):323-372
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Th1 vs Th2 ????
1. cytokines, IL-12, IFNand IL-42. Costimulatory signal3. The nature of peptide:MHC
Cell mediated (IgG) Humoral , IgM,IgA, and IgE
The stages of activation of CD4 T cells
The differentiation of CD4 T cells into Th1 or Th2 determine whether humor or cell-mediated immunity will be dominate