Chapter 11- Book Integrated dynamics of innate and adaptive immune system

Innate lymphoid cells

ILCs

Lack antigen specific receptors

SImilar to CD4 + CD9 T cells

Most abundant in barrier tissues

Primary immune response vs secondary response

Primary: When a pathogen is encountered for the first time

Secondary: second time, provides long time protection through immunological memory

Acute infection stages

1. Infectious agent colonizes and replicates- the innate immune system is initiated after detection

2. Antigen presentation by dendritic cells to lymphocytes→ adaptive immune response is triggered→ pathogen continuous to grow, restrained by innate response. AT this stage: immunological memory starts to be induced.

3. After 4-7 days effector cells and molecules of the adaptive immune response begin to contribute to the host response and act to clear infection.

4. When infection has been cleared an antigen becomes undetectable → immune response ceased but antibodies and T and B memory cells provide lasting protection.

ILCs

Cytokines produced by innate sensor cells activate ILCs

Cytotoxic ILCs: Viruses→IL-12 and IL- 15 → NK cell→ IFN-gamma

Group 1 ILCs: Intracellular bacteria→ IL-12 and IL-18 → ILC1→ IFN-gamma

Group 2: Parasites→ ILC2→ IL-13 and IL-5

Group 3: Extracellular bacteria→ ILC3→ Il-17 and IL-22

Innate sensor cells

Secrete cytokines which activates ILCs which secreted cytokines

Ex: dendritic cells, macrophages, epithelial cells

ILCs + T helper cells

ILC cells and TH cells coordinate their functions to eradicate the pathogen

ILC1 and TH1→ macrophages are enhanced

ILC2 and TH2→ enhance eosinophils, basophils and mast cells

ILC3 + TH17→ enhance neutrophils

Cytotoxic response

Characterized by actions of NK cells and CTLs→ specialized in killing cells with intracellular pathogens, stressed or damaged cells, tumor cells.

NK cells can be armed by IgG for ADCC

Produce IFN-gamma→ activated macrophages

Type 1 response

Characterized by ILCs (group 1), YH1 cells → opsonizing IgG antibody isotypes and macrophages

Type 2 response

Characterized by ILC (group 2), TH2, IgE, innate effector cells: eosinophils, basophils, mast cells

Induced by multicellular parasites

Type 3 response

Characterized by ILCs (group 3), TH17, opsonizing IgG isotypes, neutrophils

Respond to extracellular fungi or bacteria

Characterization of ILCs

Respond rapidly

Expand in number

Nonmotile→ bind barriers

NK cells

Produce IFN-gamma

Cytotoxic granules with perforin and granzymes

Circulate the blood

Mobile

Inhibitory and activating receptors

Have no antigenic receptors but can by IgG to their Fc receprtor

TH1 + ILC1

Lack cytotoxic granules

Clearance of intracellular mostly

Release IFN-gamma

IL-12 + IL-18→ induce ILC1 production of IFN-gamma→ induce killing through macro

ILC3

Extracellular bacteria and fungi

Th17

Responsive to IL-23, IL-1Beta→ leads to IL-17 and IL- 22

Activation of ILCs

Innate sensor cells produce (when pathogen invades) cytokines which activates the ILCs→ recruit innate effector cells before CD4 and CD8 cells arrive (work similar)

Effector T cells and adhesion

Change their surface molecules allowing them top sites of infections

Naive T cells stay in lymph nodes through binding of L-selectin to carbohydrates on HEV

After encounter with pathogen many diff effector cells loose L-selectin→ leave the lymph and express VÖA-4 instead (integrin) + LFA-1 which bind to VCAM-1 and ICAM-1 in infected site

TH1 response-macrophages

Enhance macrophages to kill their intracellular pathogen

Heighten their microbicidal function

Macro display peptide on MHC class 2 molecules→ TH1 cells recognize

Require signal by IFN-gamma R + IFN gamma, CD40+CD40L

• MHC class 2 peptide+ TH1

Granulomas

Pathogens incompletely killed by a TH1 response in macrophage

Gives rise to a chronic, low level infection that requires an ongoing TH1 response to limit the spread of pathogen

Granuloma is formed=microbes are held in a macro surrounded by activated lymphocytes

Fuse of macro leads to multinucleated giant cells

TH2 response

In response to helminths and parasites

TH2 cells produce IL-13 induce mucus→ prevents adherence

Recruits macrophages + mast cells

Generation of IgE→ binds FC epsilon R on mast cells, eosinophils, basophils→ antigen specific recognition and activation

Th17 cells and type 3 response

Clearance of extracellular bacteria and fungi

Produces IL-17

Production of antimicrobial peptides, chemokines

What happens with T effector cells after infection is cleared?

When a pathogen is eliminated→ antigen is gone→ most T effector cells undergo apoptosis

The cells that survive turn to be memory T cells

1. Intrinsic pathway of apoptosis:IL-2 production loss + loss of IL2R→ apoptosis

2. Extrinsic (death) patway of apoptosis→ Fas signaling → DISC→ apoptosis

Memory T cells subsets

Central memory T cells

Effector memory T cells

Tissue resident memory T cells

Express IL-7Ralfa→ respond to pro survival cytokine Il-7

Difference: Naive T cell require signals from self peptide: self MHC and IL7 for survival

Effector memory T cells→ require IL-7 but not as dependent on peptide:self MHC for survival

Memory B cells

Response is more rapid and higher affinity for antigen when memory B cells are present and not naive

Arise from GC reaction during a primary response and may have undergone isotype switching + somatic mutations OR not from GC reaction

Memory B cell marker: class switching IgG, IgA or IgE, CD27

Naive marker: IgM and IgD