Co-stimulatory molecules & T cell signalling Flashcards
What 3 signals does primary T cell activation require?
Signal 1 = TCR recognition of correct MHC peptide combination
Signal 2 = Co-stimulatory molecules engagement
Signal 3 = cytokine instruction
What 2 things do the TCR recognise?
MHC protein itself
Antigenic peptide presented by MHC protein
How does the TCR recognise MHC complexes?
TCR recognises both MHC protein and peptide antigen being presented by it
Binds with diagonal footprint that cuts across both alpha helices with the peptide in between
What is CD8 required for?
Acts as a co-receptor for MHC I
Required for T cell to make an effective response
How can TCR and CD8 bind to MHC I at the same time?
Distant binding sites
TCR binds to alpha-1 alpha-2 domains
CD8 binds to the support domains (alpha-3 and beta-2m)
What happens after TCR engagement?
Triggers signalling responses inside T cell
Up regulates expression of many genes
Main function is upregulation of IL-2 and IL-2 receptor which sets up an amplificatory loop that drives T cell clonal expansion
What does the TCR assemble with to form a signalling complex?
CD3 subunits and zeta chain/ZAP70 in ER
Allows the receptor to transmit signals into the cell following activation
What does TCR engagement trigger activation of?
Nuclear Factor for Activated T cells (NF-AT)
What does ZAP70 do?
Protein that when activated, signals the cell to release calcium from intracellular stores
Calcium will bind to phosphatase
Phosphatase will take off phosphates from NF-AT, activating it
Where is NF-AT usually found?
In the cytoplasm
What happens when NF-AT is dephosphorylated?
Goes into nucleus and can bind to its target promoters by sequence specific recognition of DNA
Binds to IL-2 promoter and turns it on
What happens when NF-AT is dephosphorylated?
Goes into nucleus and can bind to its target promoters by sequence specific recognition of DNA
Binds to IL-2 promoter and turns it on
What is central tolerance?
T cells with high affinity for self are eliminated in the thymic medulla
What T cells are allowed to leave the thymus?
Those with moderate affinity for self
These T cells are still naive (antigen inexperienced)
What are anergic T cells?
If antigen challenge not accompanied by signals of infection then T cells not activated and enter a period of extended inactivity (anergic)
Also called peripheral tolerance
NF-AT does not bind IL-2 promoter
What does peripheral tolerance help to ensure?
Lack of self reactivity
What is the second signal?
Survival signal
Upregulation of costimulatory proteins on DCs
B7.1and B7.2 (CD80 and CD86) recognised by CD28 on T cell surface
How can T cells be activated without co-stimulation?
A humanised monoclonal anti-CD28 antibody called TGN1412 is capable of binding to the CD28 receptor and activating signalling
How can co-stimulation be enhanced?
CD40L on T cells binds CD40 on DCs to increase production of co-stimulatory proteins
How can co-stimulation be decreased?
CTLA-4 on T cells binds co-stimulatory proteins on DCs with higher avidity than CD28 so acts as a decoy
Describe CTLA-4 and its significance
It is a negative regulator of T cell activation
It is constitutively expressed in Treg cells but only upregulated in conventional T cells after activation
It acts as an off switch when bound to CD80 or cd86 on the surface of APCs
What is the 3rd signal required for T cell activation?
Differentiation signal
Release of cytokines by APC to stimulate differentiation of the naive T cell
e.g. IL-6, IL-12, TGF-B, IL-4
What are the cytokines required by CD8+ cells to develop effector functions?
IL-12
Type 1 IFNs
What cytokine induces development of Treg cells?
TGF-B
What cytokine induces development of Tfh cells?
IL-6
What cytokine induces development of Th17 cells?
TGF-B
IL-6
What cytokine induces development of Th1 cells?
IL-12
IFN-gamma
What cytokine induces development of Th2 cells?
IL-4
What is the type of cytokine released dependent on?
The type of pathogen e.g DCs that are virally infected produce IL-12 and IFN-gamma which promote Th1 differentiation
