L15 - Cell mediated immune reactions Flashcards by Benjamin Chan

Which immune cells are involved in cell-mediated immunity?

T cells: Th and CTLs

Phagocytes (e.g. macrophages, neutrophils)

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List the 3 main effector mechanisms of Cell-mediated immunity?

– Cell-mediated cytotoxicity (CLT, NK)

– Chemotaxis & phagocytosis (MQ)

– Cytokine-mediated direct target cell killing (TH1)

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Classify cell-mediated immunity?

T cell dependency:

– T-dependent (specific): CLT, TH

– T-independent (early phase/ non-specific): NK, MQ

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What are the 3 subtypes of cell-mediated cytotoxicity?

Cytotoxic T Lymphocyte (CTL)-mediated Killing
Antibody-dependent Cell-mediated Cytotoxicity (ADCC)
Natural Killer (NK) Cell-mediated Killing

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Which cells are targeted by CTL-mediated killing??

Altered self cells (virus infected or tumour cells)

- Intracellular bacteria and parasites

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What antagonizes CTL-mediated killing?

antibody-binding blocks CTL recognition

Ab bind to peptide antigen directly on MHC-I of APCs

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Describe the 5 steps of CTL mediated killing?

1) Attachment – CD8+ CTL’s TCR binds to antigen presented by MHC-I on target cells

2) 2 signals:
a) TCR + MHC + CD8
b) ) Co-activators: CD80/CD86 on CTL bind CD28 on APC

3) IL-2 from T helper cells cause degranulation of CTL&raquo_space; release Perforins, Lymphotoxins and Granzymes to target cell
4) IFN-γ activates macrophages
5) Recycle CTLs for additional attacks, target cell dies when CTL detaches

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Describe the MoA of perforins?

–Released from cytoplasmic granules of CTLs

–Forms pores in the target cell membrane

–Allows granzymes, water to enter target cell

–May cause osmotic lysis

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Which cytotoxic factors induce apoptosis of target cells?

 Lymphotoxin

 Granzymes

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Describe the MoA of granzymes?

activate caspase pathway, endonuclease&raquo_space; apoptosis

toxic to actual intracellular pathogens

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Which cytokine is critical for CTL killing ?

IL-2 from Th

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Describe the process of ADCC?

Antibody-dependent Cell-mediated Cytotoxicity:

Fc Receptor on Large granular lymphocytes/ cytotoxic cells bind to Ab on target cells/ pathogens not using TCR

> > Release cytotoxic factors to directly kill

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What provides the specificity in ADCC?

Ab binding to target cell and Fc recognized by Large Granular Lymphocytes (LGL)

Ab gives Ag specificity

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Which type of cell-mediated toxicity is not specific?

Natural Killer (NK) Cell-mediated Killing

no antigen specificity

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Compare the 2 signals in NK cell mediated killing?

Signal 1 = Killer activatory receptor (KAR / lectin) on NK cell + Carbohydrate on target cell

Signal 2 = Killer inhibitory receptor (KIR / Ly49) + Self MHC-I presenting own antigen

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Describe how NK cells target abnormal cells but not own cells?

Normal cell = equal activation of Killer activatory receptor (KAR / lectin) and Killer inhibitory receptor (KIR / Ly49)
» no killing
Abnormal cell with no MHC-I or abnormal antigen&raquo_space; only activate KAR
» activate NK cell cytotoxicity

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Define which cells can activate NK cell killing?

Cells with altered MHC-I or presenting abnormal/ non-self Ag

Tumor cells (no MHC-I)
Grafts (non-self MHC-1)
Virus-infected cells (foreign Ag)

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What is the action of Fas ligand in cell-mediated killing?

Fas ligand binds to Fas on target cell&raquo_space; activate caspase, endonuclease&raquo_space; apoptosis

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List all phagocytes

– Neutrophils
– Monocytes
– Macrophages

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Describe the action of chemotatic factors in T-Independent Macrophage Activation?

Ab- Ag complex activate complement system

> > concentration gradient of chemotactic components / fragments

> > attract phagocytes to target cells (e.g. infected) / invading pathogenic microorganisms

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List 3 chemotactic molecules for T-Independent Macrophage Activation?

Bacterial components (e.g. fMLP = polysaccharide from bacterial cell wall)

Complement products (e.g. C5a)

Locally released chemokines and cytokines

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Define the 5 steps of T-Independent Macrophage Activation?

Chemotaxis
Attachment/ adherence
Uptake by phagocytosis
Destruction
Release degradation products
T-independent chemotaxis activation of other macrophages (release TNFa and IL-12) granulocytes

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Define 3 ways for phagocytes to recognize and attach to target cells/pathogens?

1) Fc receptor on phagocyte bind to Ab on pathogen
2) Complement receptor on macrophage bind to opsonized pathogen
3) Mannose receptor bind to mannose-, fucose-containing oligosaccharides on pathogen (e.g. bacteria)

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List 3 complement receptors on phagocytes?

C3b, C3bi or C1q

Describe effector mechanisms of phagocytes to kill engulfed pathogens?

Inside phagolysozymes: 1) Reactive oxygen intermediates (ROIs) e.g. superoxide anion 2) Reactive nitrogen intermediates (RNIs), e.g. nitric oxide 3) Others: e.g. complements, defensins, lysozyme, cytokines, proteases

Define the 2 reactive oxygen intermediate pathways in phagocytes?

Peroxidase-independent: generate H2O2 and anions from O2 for direct effect Peroxidase-dependent: Phagosome fuses with lysosome to generate toxic oxidants for killing

Describe the signalling event that generates Reactive nitrogen intermediates in phagocytes?

1) IFNγ >> nitric oxide synthetase (NOS) >> NOS with tetrahydrobiopterin >> NO 2) TNF >> NOS with tetrahydrobiopterin >> NO

Describe the processing of degradation products in phagocytes?

Release degradation products (with free radicals) >> antigens associate with MHC-II molecule >> present MHC-Ag complex to activate naïve T helper cells >> produce cytokines for other processes

Describe how activated macrophages signal other cells?

Type 1 cytokines (e.g. TNFα) = further recruit and activate other macrophages/ granulocytes IL-12, TNFα to NK >> NK releases IFNγ to activate MORE macrophages/ granulocytes

Describe the process of TH1-dependent macrophage activation?

1) TCR binds to MHC-II on primed macrophage with inactivated pathogens / exogenous peptide 2) CD40L (CD154) binds to CD40 on macrophage 3) Cytokine release: i) IL-2 to self-stimulate Th clonal proliferation ii) IFN-γ to activate macrophage to completely kill inactivate pathogens 3) Macrophage increase MHC, IL-12 expression to attract more Th 4) Macrophage increase lysosome formation, Phago-lysosomal fusion, Inducible NO synthase

Which process precedes Th1- dependent macrophage activation?

T cell independent activation >> unable to kill pathogen completely >> need Th1 for more enhancement of killing

List examples of cytokines with autocrine and endocrine function?

Autocrine = IL-2 Endocrine = IL-8

Define the difference between lymphokines and monokines?

Lymphokines: cytokines produced by lymphocytes •Monokines: cytokines produced by monocytes/phagocytes

List examples of interleukins and chemokines?

Interleukins: interleukin 1 -39 (IL-1– IL-39) interferons (IFN), TNF etc Chemokines: CXC (IL-8), CC (MDC), CX3C (Fractalkine)

Cytokines can activate over-lapping receptors. T or F?

False Unique receptor for each cytokine

One regulatory effect can be regulated by one cytokine only. T or F

False Pleiotropic & redundant (have multiple, overlapping cell regulatory actions)

List the source and function of IL-1?

Macrophages 1. Activate T, B cell 2. Mobilize PMNs 3. Induce acute phase proteins

List the source and function of IL-2?

``` T cells (Th1 self prolif.) Proliferation of T, NK cells ```

List the source and function of IL-4?

Mast cells >> IgE response Th2 to suppress Th1 >> Th2 dominant response >> Activate B cells

List the source and function of IL-8?

 Macrophages  T cells  Fibroblasts  Keratinocytes Chemotaxis of PMNs

List the source and function of IL-10?

Th2 cells =Activate B cell, suppress Th1 Macrophages = Suppress macrophages

List the source and function of IL-12?

 B cells = Stimulate TH1 Macrophages = Inhibit TH2

List the source and function of TGFβ ?

T cells Inhibits other cytokines

List the source and function of TNFα?

Macrophages Inflammation

Define the Th cell type for intra and extracellular pathogen?

``` Intracellular pathogens (e.g. virus, mycobacteria, some protozoa) = Th1 >> Cell-mediated immunity ``` Extracellular pathogens (e.g. bacteria, parasitic worms) = Th2 >> Ab production/ Humoral response

Which cytokines direct Th0 cells to differentiate into Th1?

IL-12(MQ, DC) IL-18 (MQ, DC, Kupffer cell) IFN-γ (T cells, NK, DC) *******

Which cytokines direct Th0 cells to differentiate into Th2?

IL-4 (mast cell, NK-T, DC) IL-6 (T, MQ) IL-10 (T, MQ, DC)

Th1 and Th2 differentation can occur simultaneously. T or F?

False Reciprocal control: Th1 and Th2 mutaully inhibit each other:

Define the cytokines involved in the reciprocal activation of Th1 and Th2?

Th1 >> IFN-γ >> inhibit TH2 proliferation Th2 >> IL-4, IL-10 >> inhibit Th1 proliferation

Which Th cell is vital for activation of cell-mediated immunity?

Th1 >> because IFN-γ has widespread effect on many effector cells

What is the role of B cells in cell-mediated immunity?

Produce antibodies >> mediate ADCC

Define the 4 phases of delayed type hypersensitivity reaction?

1) Induction phase: sensitized Th1 release cytokines after 2nd contact with same Ag 2) Inflammatory phase 3) Effector phase: activated MQ kill intracellular pathogen 4) Chronic DTH reaction: can't kill persistent pathogen (e.g. MTB), granuloatous inflammation ensues

Define the cytokines and reactions involved in the inflammatory phase of DTH?

 IFN-γ activates local macrophages  Chemokines attract / recruit more macrophages, TH1 cells

What causes chronic DTH reactions?

Persistent source of Ag (e.g. mycobacteria TB)

Define the type of inflammation that occurs in DTH?

Granulomatous inflammation >> Granuloma formation to contain persistent pathogen

Describe the composition of granulomas?

large mass of macrophages, TH1 cells + Multinucleated giant cell (Langhans type) + Epitheloid cell + Fibroblasts (producing fibrous tissue) + Peripheral lymphocytes

Compare the type of immune response mediated by Th1 and Th2?

``` Th1 = CMI Th2 = Humoral response ```

Define the 4 key characteristics of cytokines?

– Local & systemic effects – Unique receptor for each cytokine – Pleiotropic, synergistic & autocrine – Complex network

Which type of immunity defends against tumours and cause transplant rejection?

Both cell-mediated immunity • Immunity against tumors (CTLs, NKs) • Transplantation graft rejection (CTLs, NKs) – Delayed hypersensitivity reactions (DTH) – Cell-mediated cytotoxicity