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
