Co-stimulatory molecules and T cell signalling Flashcards
Primary T cell activation is tightly regulated
and requires three signals in sequence?
Describe these signals
- Signal 1 = TCR recognition of correct MHC:peptide combination
- Signal 2 = Co-stimulatory molecule engagement
- Signal 3 = Cytokine instructions
What are the two things the TCR will recognise?
- MHC protein itself (hence compatibility…)
- Antigenic peptide presented by MHC protein
How does the T-cell receptor bind to the MHC?
Binds with a diagonal footprint that cuts across both alpha helices with the peptide in between
Distant binding sites allow CD8 and TCR to bind MHC class I at the same time.
Describe this
- CD8 acts as a co-receptor for MHC class I, and is required for the T cell to make an effective response
- TCR binds to the alpha1alpha2 domains
- CD8 binds to the support domains (alpha3 and beta2m)
- Similar situation for CD4 and MHC class II
- The presence of CD4 or CD8 can help stabilize the interaction of the TCR and MHC–peptide
MHC class I – TCR engagement triggers signalling responses inside the T cell.
Describe the signalling
- Upregulates the expression of many genes, but its chief function is to up-regulate IL-2 and IL-2 receptors which sets up an amplificatory loop that drives T-cell clonal expansion
- These events are transcriptional responses
*TCR engagement triggers the activation of
Nuclear Factor for Activated T cells (NF-AT)
The TCR assembles with other proteins to form a signalling complex.
Describe the complex
- Assembly with CD3 subunits and zeta chain/ZAP70 occurs in endoplasmic reticulum
- These allow the receptor to transmit signals into the cell following activation
- ITAM = Immuno-receptor Tyrosine-based Activation Motif
Describe central tolerance and peripheral tolerance
- T-cells with high affinity for self are eliminated in the thymic medulla (Central tolerance)
- T cells with moderate affinity for self are allowed to leave the thymus
- These T cells are still naïve (antigen inexperienced)
- These T-cells are challenged by antigens at lymph nodes by Dendritic cells
- If the antigen challenge is not accompanied by “signals of infection” then the T cells are not activated; rather they enter a state of extended inactivity – they are “anergic”. This is called peripheral tolerance and it help ensure lack of self-reactivity
Describe signal 2 for T cell activation
- Initial danger signals trigger the upregulation of costimulatory proteins on dendritic cells
- The best-characterised co-stimulatory proteins
are B7.1 and B7.2 (also known as CD80 and CD86, respectively) They are constitutively expressed on DCs, but can be upregulated on monocytes, B cells, and other APCs, particularly when stimulated by inflammatory cytokines and by the interaction of microbial products with Toll-like receptors on the APC.
*The B7 co-receptors bind to CD28 and its homolog CTLA-4 (CD152), which is expressed after T cell activation.
CD28 is the main costimulatory ligand expressed on naive T cells. CD28 stimulation:
* prolongs and augments the production of IL-2 and other cytokines; and
* is probably important in preventing the induction of tolerance, a condition where the T cell is not activated and is put into a state of anergy, i.e. it is unable to respond subsequently
CD28 stimulation is essential, but it is possible to overdo it.
Describe the need for CD28 and its overstimulation
- Many conditions of the immune system are due to low numbers of activated T cells (e.g. B-cell lymphoma, autoimmune diseases such as rheumatoid arthritis)
- A humanised monoclonal anti-CD28 antibody called TGN1412 was developed – it is capable of binding to the CD28 receptor and activating signalling through it
- Stimulates activation of T cells without the need for co-infection
*Patients are given antibodies raised against CD28 which caused “superactivation” of CD28
*Triggered “cytokine storm”
Describe the tight regulation of signal 2
Enhancing co-stimulation:
* CD40 Ligand on T cells binds to CD40 on
dendritic cells to increase the production of co-
stimulatory proteins.
* Mice lacking CD40 show poor T cell
proliferation
Decreasing co-stimulation:
* CTLA4 on T cells binds the co-stimulatory
proteins on dendritic cells with a much higher
avidity than CD28
* It is an inhibitory receptor limiting T-cell activation, resulting in less IL-2 production
* Mice lacking CTLA4 die from an aggressive lymphoproliferative disorder because their, T-cells are not inactivated
Which T-cells do you find CTLA-4?
CTLA-4 is constitutively expressed in regulatory T cells, but is only upregulated in conventional T cells after activation. It acts as an “off” switch when bound to CD80 or CD86
on the surface of antigen-presenting cells
Describe signal 3 in T-cell activation
- IL-12 and type I IFNs are the signal 3
cytokines for CD8+ cells - The cytokines which provide signal 3 determine how the T cell differentiates
- Different cytokines induce the development of different effector cell subsets
Different types of pathogens cause different types of cytokine release by APCs
Describe this
- Innate immune system can detect structural and functional features of pathogens (PAMPs)
- Combinations of signals can influence which
cytokines are secreted - E.g. virally-infected dendritic cells produce IL-12 and IFNg; these promote Th1 differentiation
