T cell activation and differentiation Flashcards
Three signals for T cell activation
- T-cell receptor engagement
- Costimulation
- Cytokine signaling
T cells differentiate into
- CD8+ T cells become killer T cells (CTLs)
- CD4+ T cells differentiate into several different subsets
Where does T cell activation happen?
secondary lymphoid tissue
- spleen
- lymph node
- MALT
A successful T cell-APC interaction results in
the stable organization of signaling molecules into an immunological synapse
cSMAC
Where the TCR/MHC-peptide complexes and co-receptors centralize
pSMAC
Where adhesion molecules/bound ligands peripherally localize
How does the TCR signaling begin
With the activation of a tyrosine kinase known as Lck
Once a TCR engages MHC-peptide on the surface of an APC
the co-receptor CD4 or CD8 stabilizes this interaction
CD4 and CD8 cytoplasmic tails
guide Lck to TCR-MHC complex
Lck
phosphorylates ITAMs on CD3, which the phosphorylated ITAMs become docking sites for other signaling proteins
Various signaling cascades from signal 1
Culminate in the activation of transcription factors and their translocation into the nucleus
A costimulatory molecule required for the successful activation of naive T cells
CD28
- interacts 2nd signal CD80 or CD86 on APCs
Costimulatory signals
are required for T-cell activation and proliferation
Positive costimulatory receptors
facilitate activation
CD28
- generally involve in initial activation events in T cells
- Glycoprotein homodimer expressed on T cells
- enhances TCR-induced proliferation and survival
- Binds to CD80 or CD86 expressed by APCs
Negative co-stimulation
help turn activation off
- CTLA-4
- PD-1
CTLA-4
Bind to B7-1/B7-2 with high affinity than CD28 but shuts down signaling pathway
PD-1
CD279
- may help mediate T-cell tolerance in non lymphoid tissues
Clonal anergy
results if a co-stimulatory signal 2 is absent
- Helps provide peripheral tolerance
- This might happen if a T cell isn’t screened against a peripheral self-antigen during development
Cytokine (Signal 3)
- The outcome of T-cell activation is critically shaped by the activity of soluble cytokines produced by APCs
- PRRs signaling dictate what cytokines get produced
IL-2
- An example of an autocrine cytokine
- T cells produce the cytokine and the receptor for it
- Binding of this ligand induces a very strong proliferation signal during activation stages
Polarizing cytokines
can send the T cell down different subset development pathways
Initial activation signals 1 and 2 induce
- up-regulation of pro survival genes like Bcl-2
- Transcription of Il-2 and IL-2R (CD25)
- Activation and robust proliferation of both memory and effector T cells
Polarizing Cytokines
Regulate differentiation of T helper cells CD4+ subsets
What cytokines are nearby when the T cell is activate?
- APCs bind PAMPs/DAMPs via various PRRs, inducing cytokine secretion
- Different PRRs engaged via different antigens = different cytokines produced
Cytokine receptors
- present on all immune cells and others
- Binding is non-covalent
- usually high affinity
- induces a change in the transcriptional program of the target cell
Pleiotropic
activity induces different biological effect dependent on target cell
Redundant
activity mediates similar effects on target cell
Synergy
effect combines two cytokines activities to be greater than additive effect
Antagonistic
effect inhibits one cytokine by another’s action
Cascade
effect of one cytokine on one target cell to produce additional cytokines
Cytokines induce dimerization which leads to
- Activation of JAK tyrosine kinases by reciprocal phosphorylation
- JAKs phosphorylation STAT transcriptional factors
- STATs dimeric and translocate to the nucleus where they activate specific genes
Effector T helper subsets are distinguished by three proteins:
- Polarizing cytokine set
- Master Gene regulator
- Signature set of effector cytokines
Treg
effector cytokine: IL-10, TGF-beta
Polarizing cytokines: IL-2, TGF-beta
Master transcriptional regulator: FoxP3
Pathogen: E.coli - a gut bacterial pathogen, suppresses immune responses
TH17
effector cytokine: IL-17A, IL-17F, IL-22
Polarizing cytokines: IL-6, IL-23, TGF-beta
Master transcriptional regulator: RORgammat
Pathogen: Fungus, extracellular bacteria
TH2
effector cytokine: IL-4, IL-5, IL-13
Polarizing cytokines: IL-4, TGF-beta
Master transcriptional regulator: GATA3
Pathogen: worm
TFH
effector cytokine: IL-4, IL-21
Polarizing cytokines: IL-6, IL-21
Master transcriptional regulator: Bcl-6
Pathogen: virus (extracellular), regulare humoral immunity (B cells)
TH1
effector cytokine: IFN gamma, TNF
Polarizing cytokines: IL-12, IFN gamma, IL-18
Master transcriptional regulator: T-bet
Pathogen: virus, intracellular bacteria (e.q. listeria)
TH22
effector cytokine: IL-22
Polarizing cytokines: IL-6, TNF alpha
Master transcriptional regulator: AHR
Pathogen: S.aureus- a skin bacterial pathogen
Clonal selection
- Each B cell bears a single type of Ig receptor
- On stimulation, each cell will create a clone of cells bearing the same Ag receptor as the original
B cell antigen interaction
- induces initial activation and proliferation events in lymph nodes/spleen
- Some Ag is internalized and processed
- Interaction with helper T cells provides conditions for differentiation and memory cell production
- 3 signals
BCR signaling
- Encounter Ag in the lymph nodes and spleen
- Ag binding causes oligomerization of Ag-bound BCR molecules in the plane of the membrane
- Molecules then move into lipid rafts, which allows association of BCR ITAM signaling molecules, triggering B-cell signaling
- ITAM phosphorylation by Src family kinases
B cell Ag uptake and presentation
- Ag receptor clustering induces internalization and Ag presentation
- Once signaling begins, BCR-Ag complexes are internalized
- Internalized Ag are processed in the exogenous pathway
- Ag peptide fragments are presented in MHC class 2 molecules
- Ag engagement up regulates B cell CD40 and CD80/CD86
B cell Class switch recombination
- Occurs within lymph node/ spleen after Ag contact
Signals for switch recombination
- B cells must receive co-stimulatory signals from CD40 to engage in CSR
- Which cytokine signal is received determines isotope to be produced
Molecular mechanisms for class switch recombination
AID (activation induced deaminase) initiates CSR processes
-transcript level
