L17 - T-Cell Activation & Generation of Effector T-cells Flashcards
Describe Naive T-cell recirculation and activation?
They are released from thymus and enter the blood circulation. Thye enter a lymph node via a high endothelial venule.
They sometimes enter lymph nodes where is no antigen that is specific for the T-cell receptor, so it moves in and out of different lymph nodes until it encounters an antigen that it binds to.
This is usually at an infected site, which attracts dendritic cells that enter the lymph nodes. When T-cell binds to antigen, it receives the necessary signals from the dendritic cells and become an activated T-cell
activated T-cells move into circulation via thoracic duct of the vena cava, and move into sites of infection
State some APCs that activate T-cells?
Dendritic cell
Macrophages
B-Lymphocytes
What 3 signals are needed for T-cells to be activated/differentiated into
effector T cell?
To be fully activated and differentiated into
effector or memory T cell, the T cell needs 3
different signals:
• Signal 1: Antigen recognition
• Signal 2: Co-stimulation
• Signal 3: Cytokines
Where is the Co-stimulatory signal located?
Most commonly of dendritic cells but also provided by macrophages or B-cells
What is the co-stimulatory signal?
B7:CD28
CD28 expressed by T-cell
B7-1 (CD80) and B7-2 (CD86) molecules are expressed by the APC
How is CD40 involved in T-cell activation?
CD40 ligand binds to CD40 on Dendritic cells. This causes Dendritic cells to express B7. Activated DCs stimulate proliferation and differentiation of T-cells
Describe the effects of negative co-stimulation of activation of T-cells?
CD80 and CD86 also bind to CTLA-4, which is the master regulator for T-cell activation. It sends a string negative signal to the T-cells
What is CTLA-4 and what is the purpose ?
CYTOTOXIC LYMPHOCYTE ANTIGEN 4:
negative regulation of immune response
Reduce the inflammation after the infection has cleared
When is CTLA-4 expressed
CTLA-4 is expressed approx 2-3 days
post stimulation
For what components does CTLA-4 have high affinity for?
It has high affinity/avidity for CD80 but
opposing effects to CD28.
Therefore, competes favourably with
CD28 for ligation to CD80/86
Describe the Induction of T-cell polarisation
Dendritic cells release cytokines, that could drive the T-cell into helper type 2 (TH2) or into helper type 1 (TH1)
Describe the IL-2 induction of T-cell proliferation and how is it controlled?
IL-2 is important in activating and sustaining T-cell proliferation.
T-cell once activated, produces a lot of IL-2, which provides autocrine signalling for T-cells to allow for proliferation.
Regulatory T-cells have a higher concentration of IL-2 receptors on their surface, so they can sequester IL-2, to block this process
Describe the expression of surface molecules on T-cells over time?
Naive T-cell = TCR
Retention in Lymph Node = TCR, CD69
Proliferation = TCR, CD69, IL-2Ralpha (CD25)
Activation of dendritic cells, macrophages and B-cells = TCR, CD69, IL-2Ralpha, CD40 ligand
Control of Response = TCR, CD69, IL-2Ralpha, CD40 ligand, CTLA-4
What can a Naive CD4+ T-cell differentiate into?
Effector CD4+ T-cell
or
Memory CD4+ T-cell
What can a Naive CD8+ T-cell differentiate into?
Effector CD8+ T-cell
or
Memory CD8+ T-cell
What is the role of an effector CD4+ T-cell?
Activation of Macrophages, B-cells and other cells; inflammation
What is the role of an effector CD8+ T-cell?
Killing of infected cells an Macrophage activation
What will a naive T-cell do post TCR signalling?
Modify the expression of surface
molecules
Upregulate cytokine production
Undergo active rounds of
proliferation
Upregulate expression of pro-survival
genes
Upregulate expression of IL-2 and IL-2R-a
Differentiate into effector or
memory cells
How does TH1 polarisation occur and what is the TF that controls differentiation?
TH1 polarisation occurs in response to the presence of intracellular pathogens such as viruses and bacteria that are ingested by and destroyed by phagocytes.
Master transcription factor that
controls differentiation – T-bet
What is the function of TH1 Cells?
They produce IFNg
Help to activate
macrophages to ingest and
destroy microbes
Induce antibody class switching to IgG (opsonization).
All helpful response in
eliminating an intracellular
pathogen
How does TH2 polarisation occur and what TFs are involved?
TH2 polarization occurs in
response to phagocyte -
independent immune responses. (presence of parasites)
TH2 polarizing cytokine is IL-4,
Transcription factors: IL-4
activates STAT6 which promotes
expression of GATA 3
GATA 3 is a transcriptional
activator of IL-4 and IL-13 genes
What is the function of TH2 Cells?
TH2 cells produce IL-4, IL-5 and IL-13, effector cytokines that help eliminate extracellular parasitic infections such as worms
Promote class switching to IgE, which causes inflammatory cytokines to be released by eosinophils and mast cells.
They also increase intestinal
movement and mucus
production.
IgE also mediates allergy
Which cells produce IL-4?
• Dendritic cells do not make IL-4
• Eosinophils, basophils and mast cells
produce IL-4. ILCs also produce IL-4
