Cell fate determination in immunity – Derk Amsen
10-5
Type 1 responses (Th1) are important to kill pathogens that survive in macrophages. Th1 (induced by
IL-12 and IFN-gamma) is involved in helping CD8 cytotoxic T cells and activating macrophages to
heighten microbicidal function. Tfh cells that differentiate in type 1 response induce IgG antibodies
that neutralise virus particles.
Mycobacteria, Salmonella, Leishmania & Toxoplasma: Not killed Chronic infection in
macrophages.
They inhibit fusion of phagosomes and lysosomes by preventing acidification required to activate
lysosomal proteases. Peptides from these intracellular pathogens can be displayed in MHC II
recognised by Th1 membrane associated proteins and soluble cytokines enhance macrophage
microbicidal activity (macrophage is called classically activated or M1 macrophage).
M1 macrophages require 2 signals from Th1 cells. CD40L which sensitizes the macrophage to
respond to IFN-gamma (also made by CD8 T cells). Lymphotoxin (also made by Th1) can substitute
for CD40L. Phagosomes can now fuse with lysosomes reactive oxygen and nitrogen species
generated.
The M1 macrophage also secretes TNF-alfa stimulate other macrophages through TNFR-I.
M1 macrophages can be made more sensitive by small amounts of LPS.
Th1 cells also induce more expression of MHC II, B7, CD40 and TNF receptors on M1
macrophage.
M1 macrophage secretes IL-12 increases amount of IFN-gamma made by Th1 &
differentiation of naive CD4 into Th1 and CD8 into cytotoxic.
Cytokines and chemokines secreted by M1 macrophage recruiting other monocytes.
Th1 also recruits additional phagocytic cells to infection by making IL-3 and GM-CSF (stimulating
production monocytes bone marrow) & TNF-alfa and lymphotoxin (change properties endothelial
cells monocytes can adhere).
All together: There is a positive feedback loop via IL-12!
Mycobacteria and listeria monocytogenes escape phagosomes cytoplasm. CD8 T cells can detect
them. Pathogens released after killing antibody mediated killing or phagocytosed again.
10-6
After a Th1 cell recognises a macrophage (with antigen) secretion effector molecules (requires
several hours). The Th1 cell must adhere to the macrophage (far longer than CD8 and target cell).
The machinery of the Th1 is orientated towards the site of contact with macrophage. CD40L is also
on this site of the Th1.
All macrophages have TNF-gamma receptors, but the one in contact has highest chance to
get activated due to site polarisation.
Collateral damage is also prevented by Th1 cells only targeting infected macrophages (otherwise
inflamed tissue due to oxygen radicals, NO and proteases).
, 10-7
Some intracellular pathogens (mycobacterium) are resistant to microbicidal effect eliminated
type 1 response chronic low-level infection requires ongoing Th1 response. Chronic
coordination between Th1 and macrophages formation of granuloma.
A granuloma is the fusion of several macrophages to form
multinucleated giant cells. Lymphocytes surrounding them have
heightened antimicrobial activity. It shields of pathogens that resist
destruction. The cells in the middle die (lack oxygen and cytotoxic
effects macrophages), this is called caseous necrosis since it resembles
cheese pathology but less than no Th1 response.
10-8
Mice with deleted IFN-gamma/CD40L genes impaired macrophage activation. Other cytokines
might also be crucial in activating macrophage by Th1 though.
Depletion of CD4 T cells in HIV ineffective Th1 responses opportunistic infections
(macrophages cannot clear them). The fungi Pneumocytis jirovecci infects the lungs, normally
cleared by alveolar macrophages. You need CD4 Th1 cells to activate the macrophage by IFN-gamma
and TNF alfa.
10-9
Type 2 is against helminths, these do not replicate. They are multicellular and too large for
macrophages. IL-4 to activate Th2 can be made by a variety of cells (could be produced by iNKT cells,
mast cells, basophils, not essential).
DCs that present the antigen to naive T cells are activated by IL-13 from ILC2 cells and innate
cytokines such as TSLP (repress Th1 and Th17).
Th2 cells recruit eosinophils, basophils, mast cells and macrophages. Ligands for CCR3, CCR4 and
CRTH2 (on Th2, eosinophils and basophils) are produced by innate immune cells at helminth
infection sites (induced by IL-4 and IL-13 signalling). ILC2, Th2, eosinophils and basophils can amplify
this recruitment. Th2 cells make IL-13/4/5
IL-13 enhances production of mucus by goblet cells, activates smooth muscle cells
hypermobility and increases migration and turnover of epithelial cells in mucosa (eliminate
parasites attached to epithelium in intestines and prevents colonisation on surface).
IL-4 results in IgE antibodies. IgE binds to Fc receptors on mast cells, eosinophils and
basophils recognition and activation.
o Also production of IgG1 macrophages recognise and help type 2 response.
Il-5 from Th2 and ILC2 recruits and activates eosinophils release cytotoxic molecules (like
MBP) from secretory granules. They also respond to IgE, IgG and IgA degranulation.
IL-4 and IL-13 also differentiate macrophages into alternatively activated or M2
macrophages) participate in worm killing and tissue remodelling & repair.
M1 macrophages express INOS nitric oxide production.
M2 macrophages express arginase-1 ornithine (from proline and arginine). This increases
contractility of mucosal smooth muscle and promotes tissue remodelling and repair by stimulating
collagen production. Ornithine is also directly toxic to IgG coated larvae of certain helminths. M2
macrophages can also induce formation of granulomas that entrap worm larvae.
10-5
Type 1 responses (Th1) are important to kill pathogens that survive in macrophages. Th1 (induced by
IL-12 and IFN-gamma) is involved in helping CD8 cytotoxic T cells and activating macrophages to
heighten microbicidal function. Tfh cells that differentiate in type 1 response induce IgG antibodies
that neutralise virus particles.
Mycobacteria, Salmonella, Leishmania & Toxoplasma: Not killed Chronic infection in
macrophages.
They inhibit fusion of phagosomes and lysosomes by preventing acidification required to activate
lysosomal proteases. Peptides from these intracellular pathogens can be displayed in MHC II
recognised by Th1 membrane associated proteins and soluble cytokines enhance macrophage
microbicidal activity (macrophage is called classically activated or M1 macrophage).
M1 macrophages require 2 signals from Th1 cells. CD40L which sensitizes the macrophage to
respond to IFN-gamma (also made by CD8 T cells). Lymphotoxin (also made by Th1) can substitute
for CD40L. Phagosomes can now fuse with lysosomes reactive oxygen and nitrogen species
generated.
The M1 macrophage also secretes TNF-alfa stimulate other macrophages through TNFR-I.
M1 macrophages can be made more sensitive by small amounts of LPS.
Th1 cells also induce more expression of MHC II, B7, CD40 and TNF receptors on M1
macrophage.
M1 macrophage secretes IL-12 increases amount of IFN-gamma made by Th1 &
differentiation of naive CD4 into Th1 and CD8 into cytotoxic.
Cytokines and chemokines secreted by M1 macrophage recruiting other monocytes.
Th1 also recruits additional phagocytic cells to infection by making IL-3 and GM-CSF (stimulating
production monocytes bone marrow) & TNF-alfa and lymphotoxin (change properties endothelial
cells monocytes can adhere).
All together: There is a positive feedback loop via IL-12!
Mycobacteria and listeria monocytogenes escape phagosomes cytoplasm. CD8 T cells can detect
them. Pathogens released after killing antibody mediated killing or phagocytosed again.
10-6
After a Th1 cell recognises a macrophage (with antigen) secretion effector molecules (requires
several hours). The Th1 cell must adhere to the macrophage (far longer than CD8 and target cell).
The machinery of the Th1 is orientated towards the site of contact with macrophage. CD40L is also
on this site of the Th1.
All macrophages have TNF-gamma receptors, but the one in contact has highest chance to
get activated due to site polarisation.
Collateral damage is also prevented by Th1 cells only targeting infected macrophages (otherwise
inflamed tissue due to oxygen radicals, NO and proteases).
, 10-7
Some intracellular pathogens (mycobacterium) are resistant to microbicidal effect eliminated
type 1 response chronic low-level infection requires ongoing Th1 response. Chronic
coordination between Th1 and macrophages formation of granuloma.
A granuloma is the fusion of several macrophages to form
multinucleated giant cells. Lymphocytes surrounding them have
heightened antimicrobial activity. It shields of pathogens that resist
destruction. The cells in the middle die (lack oxygen and cytotoxic
effects macrophages), this is called caseous necrosis since it resembles
cheese pathology but less than no Th1 response.
10-8
Mice with deleted IFN-gamma/CD40L genes impaired macrophage activation. Other cytokines
might also be crucial in activating macrophage by Th1 though.
Depletion of CD4 T cells in HIV ineffective Th1 responses opportunistic infections
(macrophages cannot clear them). The fungi Pneumocytis jirovecci infects the lungs, normally
cleared by alveolar macrophages. You need CD4 Th1 cells to activate the macrophage by IFN-gamma
and TNF alfa.
10-9
Type 2 is against helminths, these do not replicate. They are multicellular and too large for
macrophages. IL-4 to activate Th2 can be made by a variety of cells (could be produced by iNKT cells,
mast cells, basophils, not essential).
DCs that present the antigen to naive T cells are activated by IL-13 from ILC2 cells and innate
cytokines such as TSLP (repress Th1 and Th17).
Th2 cells recruit eosinophils, basophils, mast cells and macrophages. Ligands for CCR3, CCR4 and
CRTH2 (on Th2, eosinophils and basophils) are produced by innate immune cells at helminth
infection sites (induced by IL-4 and IL-13 signalling). ILC2, Th2, eosinophils and basophils can amplify
this recruitment. Th2 cells make IL-13/4/5
IL-13 enhances production of mucus by goblet cells, activates smooth muscle cells
hypermobility and increases migration and turnover of epithelial cells in mucosa (eliminate
parasites attached to epithelium in intestines and prevents colonisation on surface).
IL-4 results in IgE antibodies. IgE binds to Fc receptors on mast cells, eosinophils and
basophils recognition and activation.
o Also production of IgG1 macrophages recognise and help type 2 response.
Il-5 from Th2 and ILC2 recruits and activates eosinophils release cytotoxic molecules (like
MBP) from secretory granules. They also respond to IgE, IgG and IgA degranulation.
IL-4 and IL-13 also differentiate macrophages into alternatively activated or M2
macrophages) participate in worm killing and tissue remodelling & repair.
M1 macrophages express INOS nitric oxide production.
M2 macrophages express arginase-1 ornithine (from proline and arginine). This increases
contractility of mucosal smooth muscle and promotes tissue remodelling and repair by stimulating
collagen production. Ornithine is also directly toxic to IgG coated larvae of certain helminths. M2
macrophages can also induce formation of granulomas that entrap worm larvae.
