Lc7: adequate immune responses Flashcards
mucosal tolerance - main players
- Epithelial lining
- Mucus secretion
- Antimicrobial peptides
- TGF-bet and retinoic acids for tolerance
- IgA
- Treg
- Th17 homeostatic
apical vs basolateral PPRs
- TLR on apical site IEC block inflammatory response (NFKB) strengthen barrier
- TLR on basal site IEC/intracellular induce inflammation
interplay inflammasome and TLRs
TLR signalling causes cleavage of gasdermin D (by caspases)
The fragments can form pores that cause pyroptosis of infected cells
TLR signalling also causes expression of Il1b and Il18 which can leave via the Gas-pores and cause acute inflammation
Other sensors can initiate the inflammasome (CDSs etc.) which is also initiated upon K+ influx via the Gas-pores
dead or alive bacteria response
- Inflammasome is not active without the mRNA DAMP (only in alive bacteria)
- The IL1beta gene is turned on by PRRs but not cleaved into active form by inflammasome
- It does cause low level inflammation via IL6 etc.
Rig-like reptors
- RIG-I –> uncapped ss/dsRNA with 5’ triphosphate (not in mammalian cytosolic mRNA)
- MDA-5 –> long ds RNA (longer than mammalian RNA)
leads to MAVS signalling which converges with the TRAF signalling pathway and causes expression of IFN(type 1)
STING pathway (CDSs)
- The STING (stimulator of IFN genes) pathway is an important mechanism of DNA-induced activation of type I IFN responses
- cytosolic dsDNA activates the cGAS which generates a cGAMP
- STING is an ER–localized adaptor protein which binds to cGAMP leading to its translocation to the Golgi apparatus.
- STING activates the TBK1 kinase, which phosphorylates the IRF3 transcription factor, leading to type I IFN gene expression
DCs: homeostasis or inflammation?
- In homeostasis there is a lot of TGF-beta and the DCs that pick up commensal antigens will cause activation of Tregs and homeostatic Th17
- Infection occurs and inflammatory cytokines are produced
- The tissue will no longer be tolerant DCs will start to induce Th1 and inflammatory Th17 cells
DC subsets
- Classical DCs (cDCs), also called conventional DCs, are the major type of DC involved in capturing protein antigens of microbes that enter through epithelial barriers and presenting them to T cells.
cDC1 –> cross-presenting
cDC2–> major type (CD4+ inducer) - Plasmacytoid DCs (pDCs) produce the antiviral cytokine type I interferon in response to viruses. (resemble plasma cells)
- Monocyte-derived DCs (MoDCs) are similar in function to classical DCs, only they are derived from monocytes.
- Langerhans cells are DCs that are found in the epidermis. They share similar functions to classical DCs but they are developmentally related to tissue-resident macrophages.
- (Follicular dendritic cells (FDCs) are not actually dendritic cells. They have dendritic morphology, but they are not derived from bone marrow precursors and do not present antigens to T cells.)
V(D)J recombination
- process through which TCRs and BCRs are acquired
1. Chromatin opened in specific RSS (recombinase signal regions) regions synapsis
a. RAG1/2
2. RSS segments brought next to one another
3. Double-stranded breaks introduced by RAG1/2
4. Hairpin ends opened by ARTEMIS
5. Nucleotides added/removed at broken ends by TdT
6. Processed ends ligated
T-cell activation
- Requires 2 signals (and later a 3rd for the differentiation)
1. Antigen recognition TCR recognizes MHC-peptide
a. MHC1 only 10 amino acids
b. MHC2 20 amino acids
- Co-stimulation CD28 binds B7
a. B7 is only expressed when the DCs has encountered pathogen/DAMP on PPR
- If there is only signal 1 than the T-cell might be eliminated
MHC2 presentation
- uptake of proteins
- endosomal/lysosomal degradation
- synthesis of MHC2 molecules (li molecules prevent ER peptides from binding to it)
- transported from ER-golgi-endosome
- processed peptides bind to MHC2 (li is cleaved to CLIP and removed by HLA-DM)
- expression at cell surface
MHC1 presentation
- Synthesized proteins are degraded by the proteasome
- Produced peptides are transported to ER via TAP
- Tapasin brings MHC I close to TAP (bound in ER membrane)
- ERAP trims peptides to 8-10 AA
- Peptides bind to MHC class I
cCD1 can do both MHC1 and MHC2
T-cell proliferation
upon TCR/MHC and B7/CD28 signalling the naive T cell starts to proliferate:
- anti-apoptotic proteins
- cyclins expression
- and IL2 release and IL2R expression is increased
- IL2R also becomes high affinity (alfa-chain)
- IL2-induced T cell expansion follows
enhanced DC/Tcell (CD4)signalling
TCR/MHC(antigen) interaction can induce CD40L expression on T cell causing more B7 expression on DC and more cytokine release
Thelper differentiation
(intracellular pathogen) IL12 –> Th1
(extracellular) TGF-beta (weird cus normally anti-inflam), IL6, IL12 –> Th17
TGF-beta –> Treg
(parasites) IL4 –> Th2
Thelper effector cytokines
Th1 –> IFNy
Th17 –> IL17 and IL22
Treg –> IL10
Th2 –> IL4, IL5 and IL13
B-cell activation
- BCR binds antigen
- costim: C3d-CR2 or PAMP/PRR or BCR crosslinking (carb antigen)
isotype switching
- Signals required for isotype switching:
1. Cytokines
2. CD40 triggering both provided by Tfh cells (Th1/Th2)
IL4 and IL13 –> IgE
IL21>IL4 –> IgG
mucosal cytokines like TFGb –> IgA
cytokines determine which region will be excised and which Ig is produced
DNA opens up to AID
AID turns C–>U
U is reoved by UNG
APE1 makes cleaves at abasic sides
affinity maturation
- somatic hypermutations in germinal centres to create higehr affinity antibodies
- B-cells mutate their variable chain when proliferating and only the high affinity BCR will survive
o Follicular DC keep antigens for a long time to present to B-cells
o B-cells take these antigens up if their BCR is high-affinity
o They present the digested peptide antigen to Tfh cells and will survive - Process not completely clear
o AID is involved
o Up to 10 amino acid substitutions
fungal infection
- Fungal PAMPs lead to IL6 and IL23 production
- Development of Th17 and ILC3 (inflammatory)
- IL17 and IL23
- IL22: AMP and barrier function
IL17: AMP and inflammatory cytokine repsonses
viral infection
- viral PAMPs lead to TLR signals
- MyD88 and TRAF
- inflammation and type 1 IFN (not only antiviral)
IFN response:
1. bind to IFNR
2. PKR –> inhibit translation factor
3. 2’ 5’ oligo A synthetase –> RNase L
4. GTPases
IFNy
- released by Th1, ILC1 and by NK-cells and CD8 cells (in response to IL12)
- increases capacity macrophages to kill phagocytosed bacteria
- stimulates Th1 differentiation
- increases MHC class I expression
Th1 and CD8+
- Via cytokines delivery to the naïve CD8 cells
- Via CD40L-CD40 binding to increase co-stimulation of the APC
parasite infection
Th2 and Tfh release IL4,IL5andIL13
IL4 and 13: alternative macrophage activation (M2)
IL5: eosinophil
IL4 and 13: mucus and peristalsis
Il4 and 13: IgE (IgG4) –> mast cell
M1 and M2
PRR ligands and IFNy –> M1:
- antimicrobial
- phagocytosis
- inflammation
IL4 and IL13 –> M2
- IL10 and TGFb
Tfh differentiation
Strong TCR activation by DCs > transcription factor B-cell lymphoma 6 (Bcl-6) –> dictates the first signal to shift from Th1/2 to Tfh
Reduced IL-2Ralpha prevents strong proliferation
CXCR5 upregulation directs them to the B cell follicles.
ICOS-ligand on B cells triggers ICOS on T cells promoting the differentiation to Tfh
