HIS15 Cell Mediated Immune Reactions Flashcards
Cell-mediated immune reactions
- ***Localised reaction (as opposed to Ab-mediated systemic (Humoral) reaction)
- Immune reactions mediated primarily by immune cells (esp. T cells)
- Ab and other humoral factors: Subordinate roles
- AKA Cell-mediated Immunity (CMI)
- ***Innate + Adaptive immune responses
- Basic elements and Effectors mechanisms:
- T cells (induction and maintenance of CMI) —> Specificity by TCR for immune recognition reactions
- Helper T cell (Th) —> Cytokines
- Cytotoxic T cell (CTL) —> Target cell killing - Phagocytes
- Macrophages, Neutrophils etc.
—> Kill / inactivate pathogens / infected cells directly
—> Play roles in bridging innate and adaptive immunity —> present Ag on MHC to TCR of T cell
Classification of CMI
According to:
- T cell dependency
- T-dependent (specific) —> CTL, Th
- T-independent (early phase / non-specific) —> NK, MQ - Main effector mechanisms
- Cell-mediated cytotoxicity (by CTL, NK)
—> CTL-mediated Killing
—> ADCC
—> NK cell-mediated Killing
- Phagocytosis (by MQ, Neutrophil)
—> T-dependent Macrophage activation
—> T-independent Macrophage activation - Cytokine-mediated direct target cell killing (by Th1)
—> Released from Cytotoxic cell (e.g. MQ, CTL, NK)
1. IFNγ
2. TNFα/β
***Cell-mediated cytotoxicity
3 types:
- Cytotoxic T Lymphocyte (CTL)-mediated Killing
- Antibody-dependent Cell-mediated Cytotoxicity (ADCC)
- Natural Killer (NK) cell-mediated Killing (***INNATE)
Cytotoxic T lymphocytes (CTL)
- Mainly CD8+ T cells
- MHC class I restricted (i.e. recognise intracellular / endogenous Ag) (~90% CD8+ T cells are MHC class I restricted)
- Activation of CTL requires 2 signals
1. TCR (interact with MHC-I) —> include CD8 co-receptor
2. ***CD28 (interact with CD80/CD86 on APC)
- CTL-mediated killing
***Via TCR
T cell mediate cytolysis of Target cells which present Ag (but not nearby normal cells)
- Virus infected cells —> e.g. viral protein
- Tumour cells —> e.g. mutated tumour Ag
- APC with Intracellular bacteria / parasites —> e.g. peptide antigen
5 stages of mechanism of Target cell killing by CTL
- CTL bind to Target cell (MHC class I for CD8+ T cell lysis)
- TCR-MHC interactions and CTL activation
- CTL introduce “lethal hit” via activation of target cell’s apoptosis / through a “toxic hit” of chemicals
—> Cytotoxic factors release (***Perforin, Granzymes, Lymphotoxin)
—> Perforin: introduce transmembrane pores on Target cell —> Osmotic lysis
—> Granzyme: enter through pores and kill Target cell by activating apoptosis
—> Lymphotoxin: programmed cell death - Target cell death once CTL detached
- Recycling of CTL for additional attacks
Other mechanisms
1. CTL can also receive Cytokines (***IL-2) from Th cells
—> further stimulated
—> Clonal expansion with specificity to Ag presented by APC
- Activated CTL also release ***IFNγ for activation of macrophages
Perforins and Granzymes
Both primarily used for lysis of cells infected with ***intracellular pathogens
Perforins:
- released from cytoplasmic granules of CTLs
- form pores in target cell membrane
- ***allow granzymes to enter
- also cause ***osmotic lysis
Granzymes:
- Protein molecules that ***activate apoptosis
- some are also ***toxic to intracellular pathogen itself (e.g. Granulysin)
Others: Fas - Fas ligand binding also induce apoptosis (via Caspase and Endonuclease reactivation)
CTL recognition blocked by Ab binding
Ab binding:
1. Directly to microorganism surface
2. MHC / peptide complex
—> block access of CTL to MHC / peptide complex
—> CTL cannot be activated
—> Antibody-dependent Cell-mediated Cytotoxicity (ADCC) become useful
- Antibody-dependent Cell-mediated Cytotoxicity (ADCC)
- Mediated by ***Large Granular Lymphocytes (LGL) (e.g. NK cells)
- Cytotoxic cells possess ***Fc receptors
—> Ab as a bridge between effector cell (LGL) and target antigen
—> Antigen specificity by Ab
—> Ab Fc receptor (FcR) on LGL recognises Ab on abnormal cell
—> Activated LGL
—> Release cytotoxic factors (Perforin, Granzymes) to kill cell
Target cells:
- Virus infected cells
- Tumour cells
- APC
- Microorganism itself (no need APC, Ab directly bind to Ag on microorganisms)
- Natural Killer (NK) cell-mediated Killing
***NO Ag specificity —> Innate response
NK cells:
- 2 receptors: KAR (killer activatory receptor) + ***KIR (killer inhibitory receptor)
- KAR (Lectin): recognise Carbohydrate on cell surface —> Killing signal
- **KIR (Ly49): recognise **Self MHC-I (normal MHC) —> Inhibit Killing signal
Normal cell:
NK cell both KAR + KIR activated —> NK cell not activated —> No killing
Abnormal cell:
**Change in MHC/peptide complex (e.g. **MHC not expressed) —> KIR not activated —> no KIR signal, NK cell only KAR activated —> NK cell activated —> Killing by cytotoxic factors (Perforin, Granzymes)
Target cells:
- Tumour cells (no MHC-I)
- Grafts (non-self MHC-I)
- Virus-infected cells (foreign Ag)
***Summary of CTL-mediated killing, ADCC, NK cell-mediated killing
CTL-mediated killing:
- CTL
- ***TCR recognising MHC/peptide complex
ADCC:
- LGL
- ***Fc receptor recognising Ab (bound on MHC/peptide complex OR Ag of microorganism)
NK cell-mediated killing:
- NK cell
- KAR recognising Carbohydrates / ***KIR recognising MHC-I
Phagocytes
- ***Innate immunity
- Recognition + Elimination of invading pathogens
1. Neutrophils
2. Monocytes
3. Macrophages
***T cell-independent Phagocytosis / Macrophage activation
T-independent Macrophage activation: ***靠Complement + Ab + Bacteria component + IFNγ from NK cell
- Chemotaxis
- Chemotactic components from **Complement (Ab-Ag complex) / **Ab / ***Bacteria itself
—> create concentration gradient
—> concentration gradient attract phagocytes to migrate towards bacteria - Adherence, **Membrane activation, Phagocytosis
- **change in surface of phagocytes (e.g. Complement receptor, Fc receptor, Adhesion molecules)
—> able to attach to microorganism
—> initiation of Phagocytosis
—> Phagosome - Destruction
- Lysosome fuse with Phagosome
—> ***Lysosome release toxic substances
—> killing and digestion of microorganism - Release of degradation products
—> degraded Ag bind to MHC-II molecules
—> present on surface of Phagocyte as MHC-II/Ag complex (i.e. APC)
—> bridge between Innate and Adaptive immunity
Chemotaxis
- Bacterial components (e.g. Formyl-Methionyl-Leucyl-Phenylalanine (f-Met-Leu-Phe / fMLP))
- Complement products (e.g. ***C5a, triggered by Ab-Ag complex)
- Chemokines and Cytokines (locally released from other immune / tissue cells)
Mechanisms of recognition in Phagocytosis
-
**Fc receptor-mediated
- recognise **Ab on pathogens bind to Fc receptor on phagocytes -
**Complement receptor-mediated
- e.g. C3b, C3bi / C1q receptors on macrophages
- recognise **Complement deposited on pathogens (via alternative / classical / lectin-induced pathway) bind to Complement receptor -
**Mannose receptor-mediated
- recognise mannose and fucose-containing **oligosaccharides on pathogen surface (e.g. cell wall)
***T-independent Macrophage activation: Cytokine release from Macrophage and NK cell
NK cell
1. ***IFNγ —> attract Macrophage —> adhere to and squeeze through endothelium to infection site
Macrophage 1. ***IL-12 —> activate NK cell + Th 2. ***TNFα —> activate NK cell —> attract Granulocyte —> adhere to and squeeze through endothelium to infection site
***T-dependent Macrophage activation
Late phase of phagocytosis
T-dependent Macrophage activation: ***靠IFNγ from Th
Macrophage (Primed with inactivated pathogens) (本身食左野):
—> Ag presented on MHC-II + Co-stimulatory signal (CD40)
—> Activate Th1 (with CD40L)
—> Th1 produce IL-2 (—> IL-2 activate Th1 itself (自己stimulate自己) —> Clonal expansion of Th1)
—> Th1 release IFNγ
—> activate Macrophage
—> further enhance Antimicrobial function (再增強自己食野能力)
- **Effects:
1. MHC expression ↑
2. Lysosomes formation ↑
3. Phago-lysosomal fusion ↑
4. Inducible NO synthase (iNOS) —> ROS ↑ for pathogen killing
5. IL-12 production ↑ —> further stimulate Th (+ve feedback)
Effector mechanisms for Macrophage-mediated killing of microorganisms
- Reactive Oxygen Intermediate (ROIs) (majority)
- by Myeloperoxidase in Lysosome / Catalase from Peroxisomes
- Superoxide anion - Reactive Nitrogen Intermediate (RNIs)
- Nitric oxide (by nitric oxide synthase) - Other mediators
- Defensins, Lysozyme, Complements, Cytokines, Chemokines (e.g. IL-1, TNF, IFNγ)
End result:
- Bacterial killing
- Recruit + Activate additional immune cells
Cytokines classification
Small pharmacological active products (peptides / glycoproteins) of cells (mainly by Th cells)
- Lymphokines
- cytokines by lymphocytes - ***Interleukins
- IL1-39
- Interferons (IFN)
- TNF
- etc. - Monokines
- cytokines by ***monocytes/phagocytes - Chemokines
- cytokines with ***chemotactic function
- CXC (IL-8)
- CC (MDC)
- CX3C (Fractalkine)
***Cytokines principles of action
Function:
- Activate MQ, lymphocytes
- Direct killing of infected / tumour cells
Features:
- Local / Systemic effects
- Autocrine action (e.g. IL-2: 自己stimulate自己)
- Paracrine action (local, short distance)
- Endocrine action (travel in circulation) - ***Unique receptor for each cytokine
- **Pleiotropic (different actions by 1 cytokine) + **Redundant (multiple, overlapping cell regulatory actions)
- ***Synergistic (cooperative effect)
- dual activation
- induction of receptors for other cytokines - Complex network
- a single cell can secrete / susceptible to >=1 cytokine - Bind to cytokine receptor
—> signal transduction
—> trigger ***gene activation (e.g. adhesion molecules, NO synthase, cytokine receptors, MHC molecules)
—> biological effects (e.g. adhesion, phagocytosis, activation, proliferation, differentiation, growth inhibition)
Cytokine-mediated Direct Target cell Killing
Released from Cytotoxic cell (e.g. MQ, CTL, NK)
- TNFα/β
- IFNγ
***Th cell subsets and their reciprocal control
Th0 (Naive T cell)
簡單而言:
- Intracellular pathogen —> Th1 —> IFNγ (inhibit Th2) —> CMI
- Extracellular pathogen —> Th2 —> IL-4 (inhibit Th1) —> Ab production
- Intracellular pathogens (e.g. virus, mycobacteria, protozoa)
(—> IL-12, IL-18, IFNγ)
—> Th1
—> **IFNγ, IL-2, TNFα (Th type 1 cytokine) —> **Inhibit Th2
—> Cell-mediated immunity - Extracellular pathogens (e.g. bacteria, parasitic worms)
(—> IL-4, IL-6, IL-10)
—> Th2
—> **IL-4, IL-5, IL-10 (Th type 2 cytokine) —> **Inhibit Th1
—> Antibody production
Type of immune effector mechanism induced (i.e. Th1 / Th2) may determine outcome of infection
E.g. Leishmania infection (intracellular pathogen)
—> Th1 cytokine profile
—> CMI
—> macrophage activation
—> disease resolved
If condition changed and favour Th2
—> Th2 cytokine profile
—> progressive disease due to CMI suppression
***Th1 cells
Orchestrate CMI through
- Cytokines secretion (e.g. IFNγ, TNFα, IL-2)
- Enhances activity of Macrophages, Neutrophils, CTLs
- Causing B cells to produce Ab subtypes (e.g. IgG) capable of mediating ***ADCC
CMI in Delayed Type Hypersensitivity reactions (DTH)
DTH: immune reactions that show peak responses at 24-72 hours after antigen administration
- e.g. TB infection, Contact dermatitis
- Important for resistance to intracellular pathogens
- Specific ***T cell responses to Ag (e.g. TB)
Mediator: Th1
Effector: MQ
- Induction phase
- antigen-sensitised T cells release IFNγ following a secondary contact with same antigen - Inflammatory phase
- IFNγ induce inflammatory reactions (e.g. Contact dermatitis)
—> activate and attract MQ
—> MQ release IL-12 to attract more Th1 - Effector phase
- activated MQ kill intracellular pathogens - Chronic DTH reaction
- persistent sources of Ag (e.g. Mtb)
—> large mass of MQ and Th1
—> granuloma formation (Th1 + Epitheloid cell + Multi-nucleated giant cell + Mtb)
—> Th1 contain tuberculoid infection
CMI and clinical relevance
- Immunity against tumours (CTL, NK)
- Transplantation graft rejection (CTL, NK)
- Delayed type hypersensitivity reaction
- Cell-mediated cytotoxicity
