dont know (3) Flashcards
L14- Th1
Targeting things inside your cells e.g: viruses
I.e: intracellular pathogens bacteria voruses and fungi.
Strong TCR
Information captured by dendritic cell and express mhc class 2 and secrete il-12: acting as signal 3 to direct differentiation into th1. So il-12 will be recognised by the il-12 receptor (signal 3) in the presence of a strong tcr signal and costimulation. Then sarc proteins will move and then the master transcription factor for th1 which is T-bet will be in promoters for genes that encode effector function proteins for the cell which are: IFN-Y (Macrophage activation
and antigen presentation
Activate NK and T cells
Class switch to IgG2a)
IL-2 (T and NK cell proliferation)
TNF-ALPHA - a very potent inflammatory cytokine (Macrophage activation from monocytes)
These are all soluble mediators (cytokines).
This happens in tertiary and secondary lymphoid organs.
L14- population of Tregs?
Depending on their origin:
- Thymus derived – natural Tregs (nTregs)
- Upon differentiation in periphery – induced Tregs (iTreg)
L14- Tfh?
Immunity: B cell help
in the GC
NO CD28
ICOS-ICOSL
Secrete IL-6 , IL-27
Have IL6R
Master TF: Bcl6
Migration: CXCR5
Effector mechanism: IL-21
B cell memory, plasma cell differentiation
Effector cells and mechanisms: interactions with B cells
L14- iTregs?
Immunity: Regulation of
the immune
response
Molecular programme:tolerogenic DC (in situations where antigen is ours like microbiota which is foreign but do not want to fight as required for living) secrete (TGF beta)
IL-2
Treg has IL2R
Master TF: FoxP3
Constitutive CD25 and CTLA-4
(CD25 allows compeittion for IL-2 with effector T cells) deplete effector cells from signal 2 by expressing ctla-4 which binds to b7 with high affinity.
Effector mechanism:
Cytokine production:
IL-10 - block effector mechanisms
Inhibits macrophage
activation
Inhibit DC function
IL-35
Promotes Breg and
Treg function
TGF-B
Other suppressive mechanisms:
Competition for IL-2
- Competition for B7
so effector t cells do not have enough to grow and their effector functions are blocked.
- Adenosine Production: iTregs express CD39 and CD73, enzymes that convert extracellular ATP (a pro-inflammatory signal) into adenosine (hydrolysis), which has immunosuppressive and anti-inflammatory effects.
- Direct killing (perforin,
granzymes) - not true apparently? possible context dependent
L14- Th17?
Immunity against: EXTRACELLULAR
PATHOGENS
Bacteria
Fungi
Molecular
programme
In the presence Strong TCR and co stimulatory signal in the lymph node, nascent naive t cell will differentiate to th17 by expressing il-6 receptor.
Dc in lymph node screte IL-6
(TGF)
Have IL6R
Master TF: RORc2
Migration: CCR6
Effector
mechanism
Neutrophil recruitment
NK cell activation
Antimicrobial peptides
IL-17
IL-22
Proliferation epithelia
CCL20
Th17 cell recruitment
Effector cells and mechanisms:
Neutrophils
Macrophages
Fibroblast/epithelia
NK cells
L14- Th2?
IgA- most abundant immunoglobulin in the body. Characteristic: secreted. Immunoglobulin of the gut, keeps your microbiome ? and IgE bind and activate macrophages and complement?
EXTRACELLULAR
PATHOGENS
Helmints
Weak TCR
secrete IL-4 - signal 3 recognised by IL4R
Master TF- Gata-3 is activated
Effector mechanism:
IL-5
B cell proliferation
Class switch IgA
Eos+Bas activation
IL-13
B cell proliferation
Class switch IgA
Mucus production
Muscle contractility
IL-4
B cell proliferation
Class switch IgE
Mast cell activation
M2 macrophage activation
Immunity Effector cells &
mechanisms
Eosinophils
Basophils
Mast cells
IgA/E production
L20- Tumour evasion strategies?
Tumor cells downregulate MHC class I or stop expressing certain proteins to avoid immune recognition.
Cancer cells secrete suppressive factors (e.g., TGF-β) that inhibit T cell activity.
They upregulate inhibitory ligands to suppress immune responses.
L20- Immune synapses in cancer?
Defective immune synapses in cancer:
T cells from cancer patients exhibit defective F-actin immunological synapses, reducing their efficiency.
L20- why are PD-L1 overexpressed?
Mechanisms for why the ligands are overexpressed in cancer: cancer cells have oncogenic protein pathways which are activated e.g: akt. When tumour cell has oncogenic signalling, pd-L1 is expressed at very higher levels. Called innate resistance or intrinsic resistance:
Intrinsic resistance refers to the constitutive expression of PD-1 ligands because of genetic alterations or activation of oncogenic pathways in cancer cells.
Constitutive expression of PD-1 ligands - amplification of chromosome 9p24.1 in Hodgkin’s lymphoma which encodes PD-L1, PD-L2 and JAK2.
EBV viral infection is another mechanism of PD-L1 overexpression in the lymphomas.
Alternativley: adaptive resistance. T cell recognises signal 1 and secrete ifn-y which is taken up by tumour cell, triggers stats signalling that elavates pd-L1.
Adaptive resistance refers to the induction of tumour PD-L1 expression in response to cytokine IFN-γ secreted by proximal T cells.
Adaptation of tumor cells upon sensing an inflammatory immune/T cell response.
Inhibition of T cells also mediated by PD-L1+ myeloid cells or DCs in the tumour microenvironment
