Lecture 22 Flashcards
How do TH1 cells help macrophages fight intracellular pathogens?
- TH1 cells recognize pMHC class II on macrophages.
- TH1 cells use CD40L to bind to CD40 on macrophages.
- TH1 cells secrete IFNγ, which boosts macrophage antimicrobial activity.
- This also promotes production of TNFα by macrophages, further enhancing their ability to kill pathogens.
What are two strategies pathogens use to persist inside macrophages?
(1) Inhibit fusion of phagosome & lysosome (prevents exposure to lysosomal enzymes).
(2) Prevent acidification (lysosomal proteases require low pH to activate).
What receptor-ligand pair is involved when a TH1 cell activates a macrophage?
- CD40L on TH1 cell binds to CD40 on macrophage.
What cytokine does a TH1 cell secrete to activate macrophages? What does it do?
- IFNγ
- Boosts macrophage antimicrobial activity.
After TH1 activation, what cytokine do macrophages produce to enhance their response?
TNFα
What are M1 macrophages and how are they induced?
- Classically-activated macrophages.
- Induced in the context of TH1 responses.
- Boosted antimicrobial mechanisms.
What cytokine do M1 macrophages secrete to provide themselves with a survival signal?
- TNFα (acts via autocrine signaling to promote macrophage survival).
What does CD40L binding do for M1 macrophages?
- Activates macrophages.
- Increases expression of IL-12 (important for TH1 cell signal 3).
What cytokines work together to increase MHC I & II, CD40, B7, and IL-12 expression in M1 macrophages?
TNFα
IFNγ
How do M1 macrophages and TH1 cells create a feed-forward loop?
- M1 macrophages produce IL-12, which enhances TH1 differentiation/activation.
- TH1 cells produce IFNγ, which enhances M1 macrophage activation.
- This loop boosts both TH1 and M1 responses.
Besides TH1 cells, what other immune cells can activate M1 macrophages and how?
Effector CTLs (CD8+ T cells) can also secrete IFNγ, which activates M1 macrophages.
Under what circumstances do TH1 cells kill macrophages?
When macrophages are chronically infected and unable to clear the infection.
How do TH1 cells recognize infected macrophages?
TH1 cells recognize pMHC-II on the macrophage surface.
What ligand-receptor pair is used when TH1 cells trigger apoptosis of infected macrophages?
FasL on TH1 cell binds Fas on infected macrophage.
This triggers apoptosis.
What happens to bacteria released from an infected macrophage after it is killed by a TH1 cell?
The released bacteria are phagocytosed by freshly recruited macrophages.
What cytokine do TH1 cells secrete to help CD8+ T cells, and what does it do?
- IL-2
- Stimulates CD8+ T cell proliferation and differentiation into cytotoxic T lymphocytes (CTLs).
Where does TH1 help for CD8+ T cells happen?
In the secondary lymphoid organ (usually the lymph node).
How do CTLs recognize infected macrophages?
By binding to pMHC-I on the macrophage surface.
What do CTLs do to infected macrophages after recognizing pMHC-I?
Kill the infected macrophages.
How do TH1 cells stimulate increased differentiation of monocytes in the bone marrow?
- TH1 cells secrete IL-3 and GM-CSF, which act on precursors in the bone marrow.
- This is an endocrine effect (cytokines circulate through the blood to reach bone marrow).
What type of signaling is it when IL-3 and GM-CSF act on bone marrow precursors?
Endocrine signaling (cytokines travel through the blood to a distant site).
How do TH1 cells recruit more macrophages by changing adhesion molecule expression?
- TH1 cells secrete cytokines that alter the expression of adhesion molecules on endothelial cells.
- This facilitates the recruitment of more macrophages to the infection site.
How do TH1 cells recruit macrophages to the site of infection?
TH1 cells secrete CCL2, a chemokine, which attracts macrophages to the infection site via chemotaxis.
How does chronic M. tuberculosis infection lead to granuloma formation and what are the key features of the granuloma?
- M. tuberculosis infects macrophages in the lung, often resistant to their antimicrobial effects, leading to chronic infection.
- Granuloma formation occurs with:
(1) Core of infected macrophages.
(2) Surrounded by activated macrophages.
(3) Layer of TH1 cells on the outermost layer. - The center of the granuloma often becomes necrotic due to lack of oxygen and the cytotoxic effect of activated macrophages, leading to cell death.
What is the signal 3 for TH2 cells?
IL-4 is the signal 3 for TH2 cells.
What are the effector cytokines secreted by TH2 cells?
IL-4, IL-5, and IL-13.
What is the master transcriptional regulator for TH2 cells?
GATA-3.
What role do TH2 cells play in the immune response to helminths (worms)?
TH2 cells activate eosinophils, mast cells, basophils, and macrophages to respond to helminth infections.
What diseases are linked to dysregulated TH2 responses?
Allergies and asthma.
What is Signal 3 for TH2 cells?
IL-4 is the Signal 3 for TH2 cells
Which transcription factor is activated in TH2 cells?
STAT6 protein gets activated.
What is the master transcriptional regulator for TH2 cells?
GATA3 gene gets activated.
(Note: GATA3 is a transcription factor).
Which cytokines are secreted by TH2 cells?
IL-4, IL-5, and IL-13.
Which cells do TH2 cytokines target?
Eosinophils, basophils, mast cells, and macrophages.
How do TH2 cells aid in killing helminth parasites?
TH2 cells secrete IL-4, IL-5, and IL-13 to activate eosinophils, basophils, mast cells, and macrophages to combat parasitic helminths.
Where do helminths colonize, and how many people are infected?
- Helminths colonize the gut of humans and animals.
- Over 1 billion people are currently infected with helminths.
What type of infection do helminths usually cause?
Chronic infection.
What are the potential outcomes of TH2 responses to helminths?
Clear the pathogen (or result in chronic infection if ineffective).
How do TH2 responses impact worm burden?
Reduce worm burden through the process of “Weep and sweep.”
How do TH2 responses contribute to tissue repair?
TH2 cells facilitate tissue repair during infection.
Why are IgE antibodies important in TH2 responses to helminths?
IgE antibodies are crucial for immune responses against helminths.
How does IL-13 affect mucus production and epithelial tissue turnover?
- IL-13 increases mucus production by goblet cells and increases epithelial tissue turnover.
- This is part of the “weep” in the “weep and sweep” response.
How does IL-13 help in worm expulsion?
- IL-13 stimulates smooth muscle cells to contract, aiding worm expulsion.
- This is the “sweep” in the “weep and sweep” response.
What role do IL-4 and IL-13 play in M2 macrophage activation?
IL-4 and IL-13 are important for activating M2 macrophages (alternatively activated macrophages).
What functions do M2 macrophages serve in helminth infections?
- M2 macrophages aid in tissue repair, worm killing, and expulsion.
- They can increase smooth muscle contraction, form granulomas to entrap worms, and release toxic mediators through antibody-dependent cell-mediated cytotoxicity (ADCC).
What is ADCC and how is it related to M2 macrophages?
- ADCC (Antibody-Dependent Cell-Mediated Cytotoxicity) involves killing antibody-coated target cells by cells with Fc receptors.
- M2 macrophages can use ADCC to release toxic mediators directly onto the worm.
How does IL-5 affect eosinophils?
IL-5 activates, recruits, and enhances eosinophil differentiation.
What role do eosinophils play in helminth infection?
- Eosinophils release major basic protein (MBP) from their granules, which can kill parasites.
- They also recognize IgE antibodies bound to parasites and degranulate to kill the pathogen.
How do mast cells contribute to the TH2 response?
- Mast cells degranulate when activated by IgE antibodies bound to parasites.
- Their granules contain histamine and other molecules that increase vascular permeability, intestinal motility, and recruit inflammatory cells.
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How do mast cells contribute to the TH2 response?
- Mast cells degranulate when activated by IgE antibodies bound to parasites.
- Their granules contain histamine and other molecules that increase vascular permeability, intestinal motility, and recruit inflammatory cells.
What role do basophils play in TH2 responses?
- Basophils secrete IL-4 and IL-13, activate goblet cells, cause vasodilation, and release histamine.
- They also bind to IgE antibodies to support the type 2 immune response
How do TH2 responses relate to allergies?
- TH2 responses to allergens lead to IgE production, which binds to mast cells and basophils.
- This triggers degranulation, releasing histamine, proteases, and chemokines, causing allergic symptoms.
Why is IgE important in allergies?
IgE antibodies bind to mast cells or basophils in allergic reactions, inducing degranulation and the release of mediators that cause symptoms.
How do IgE levels in the blood relate to allergies?
- Free circulating IgE is usually very low in blood serum.
- IgE levels rise in response to parasitic infections but can also increase in allergies due to IgE-mediated reactions.
