Effector T Cells Flashcards
How can many different antigens be recognised by MHC as theres only 2 of these?
There are many different alleles for many genes and therefore polymorphism and polygeny both contribute to the diversity of MHC molecules expressed by an individual .
Can you inherit MHC haplotypes?
Yes
Gene conversion is not the same as what?
Genetic recombination
Can people have the same MHC?
No
What are immature Dendritic cells?
Phagocytes
Where are immature DC found?
Lymphoid organs and peripheral tissues
What are the two types of DC?
Conventional and plasmacytoid
What do conventional DC’s do?
Ingest and digest microbes and generate peptide antigens
Present on MHC to activate T cells with cognate TCR in secondary lymphoid tissues.
Produce cytokines in response to danger PAMPs by PRR engagement to activate other cells appropriately.
What do conventional DC 1 notice and produce?
Intracellular pathogens - they produce IL-12 and present to CD8 T-cells.
What do conventional CD2 cells notice and produce?
Extracellular pathogens and produce IL-12, IL-6 and TGF-beta to present to naive CD4+ T cells
What are the routes antigens are produced and show in DC?
Receptor mediated phagocytosis
Marocpinocytosis
Viral Infection
Cross-presentation after phagocytic or macropinocytic uptake
Transfer from incoming dendritic cells
What is the pathogen presented, MHC molecule loaded and type of naive T cell activated in receptor mediated phagocytosis?
Extracellular bacteria, fungi,
MHC2
CD4 T cells
What is the pathogen presented, MHC molecule loaded and type of naive T cell activated in macropinocytosis?
Extracellular bacteria, soluble antigens, virus particles.
MHC class 2
CD4 T cells
What is the pathogen presented, MHC molecule loaded and type of naive T cell activated in viral infections?
Viruses
MHC 1
CD8
What is the pathogen presented, MHC molecule loaded and type of naive T cell activated in cross presentation?
Viruses
MHC 1
CD8 T cells
What is the pathogen presented, MHC molecule loaded and type of naive T cell activated when transfered from incoming DC to resident DC?
Viruses
MHC 1 and MHC 2
CD 8 T cells and CD4 T cells
increased expression and co stimulatory molecules
What does antigen recognition result in?
Increased CCR7 expression and co-stimulatory molecules CD80/CD86 to enhance longevity of existing MHC 2 expression.
What binds CCR7?
CCL21 and CCL19
What forms a netwoek in the T cell zones in lymphoid tissue to enable interactions between naive T cells and DC?
Fibroblast reticular cells
What is produced in the fibroblast resticular cells which allows CCR7 bearing T cells and DC cells to meet?
CCL21 and CCL19
What happens when the T cell and the DC meet?
T cell initially bind APCs through low affinity LFA-1:ICAM-1 interactions and this signals to LFA-1 which causes a conformational change in LFA-1 increasing affinity and cell-cell contact
What forms when T-cells and DC meet?
Immunological synapse
What is Wiskott-Aldrich sydrome (X-linked)?
Increased tendency to bleed caused by a significantly reduced number of platelets. It is characterised by recurrant bacterial, vial and fungal infections. Also eczema of the risk and increased risk of developing severe autoimmune disease.
Where is WASP expressed in and what does it do?
Hematopoietic cells and plays a crucial role in actin cytoskeleton remodelling.
What are the 3 signals shown to activate naive T cells
MHC binds to T cell and the co-stimulatory molecules are CD80/CD86 which bind to CD28 on the T cells. The APC then secretes cytokines to help differentiation.
Along with CD80/86 binding to CD28 what must CD4+ T cells have?
CD40 on DC engagement with CD40L on T cells
Along with CD80/86 binding to CD28 what must CD8+ T cells have?
4-1 BBL production on DC through CD40 activation resulting in binding to 4 - 1 BB on T cells.
What is the TCR signalling activated by?
Tyrosine phosphorylation (ITAMs) at cytoplasmic regions. These are present on the cytoplasm two on each CD3 theta, gamma, delta and zeta chains and one on the CD3 gamma, delta and theta.
What does CD28 and TCR complex and signalling promote?
survival
Proliferation
Differentiation
How does CD28 and TCR promote survival?
Increases production of Bcl-X, Bcl-2
How does CD28 and TCR promote proliferation?
Increase secretion of IL-2 expression of IL-2 receptor, increased cyclins and decreased cell cycle inhibitors.
How does CD28 and TCR promote differentiation?
Multiple signal pathways
What are the signalling intermediates between CD28 and TCR before promoting survival, differentiation and proliferation?
PI-3 kinase/Akt and RAS/MAP kinase
What happens when antigens activate niave T cells?
Change of morphology, metabolism (glycolyses happens faster but theres less ATP) and cell cycle progression (this speeds up)
What IL is key for proliferation?
2
What ligand is important for full activation of innate cells?
CD40L
What preferentially binds B7 (CD80/86) and to do what?
CTLA4 to control the response.
Why do effector T cells no longer require co-stimulation?
CD4+T cells need to activate B cells and macrophages that have taken up antigen even if no co-stimulatory molecules are expressed.
CD8 T cells must be able to recognise antigen presented on cells that dont express co-stimulatory molecules.
What DC cytokines turn a naive T cell into a Th1 cell?
IFN-gamma and IL-12
What DC cytokines turn a naive T cell into a Th2 cell?
IL-4
What DC cytokines turn a naive T cell into a Th17?
IL-6, IL-23 and TGF-beta
What DC cytokines turn a naive T cell into a Tfh cell?
IL-6?
What do Th1 cells secrete?
IFN-gamma
What do Th2 cells secrete?
IL-4
What do Th17 cells secrete?
IL-17
What does Tfh cells secrete?
IL-21
What are key transcription factors induced by?
Specific STAT
Can cytokines produced by one T effector cell inhibit production of another?
Yes however there is a bit of flexibility.
How does an effector cell change into a memory cell if it doesnt die?
It changes its receptor to CD45RO
What are the 2 different types of memory cells?
Central Memory Cells and Effector memory cells
What do central memory cells express and what do they do?
Express CCR7 and remain in lymphoid tissue
What do effector memory cells do to CCR7 and what do they do?
lack CCR7 and migrate to tissue
What mediates T cells getting out of the lymph node into the tissue?
Sphingosine 1 phosphate (SIP) and S1PR)
How long do naive and antigen stimulating T cells stay in the lymph node?
12 hours - naive
3 days for antigen-stimulated T cells.
How do T cells exit the lymph node when they are not activated?
When a T cell enters the lymph node it has low levels of S1PR1 if there is no antigen recognised the S1PR1 is eventually reexpressed and detect SIP and so leaves down the gradiant towards more SIP.
How do activated effector T cells leave the lymph node?
T cells enter the lymph nodes with low S1PR1 which remains low if an antigen is present. This allows the activated T-cell to proliferate before the S1PR1 is re-expressed. This then means SIP will bind to receptor and it will flow down its concentration gradient and out of the lymph node.
What is a treatment for MS?
SIPR modulators as the T-cells wont migrate out of the lymph node
What do Thelper cells do?
Express IFN-gamma which activates macrophages which can engulf any invading pathogens.
What do Th2 cells do?
They secrete Il-4, IL-5 and IL-13 which is important in defending the body against helminths
What do Th17 cells do?
They secrete IL-17 and IL-22 which is good for stopping fungal infections and bacterial.
What do Tfh cells help with?
They secrete IL-21 and help destroy nearly all microbes by helping B cells bind and proliferate.
What do Tregs secrete and do?
Secretes TGF-beta and IL-10 and are self and microbiome derived.
What does Th1 produce which activates macrophages and enhances their killing?
IFN-gamma and CD40L
What is produced by Th1 cells to induce apoptosis of bacteria laden macrophages and why?
Fas ligand and LT-beta
In order to kill chronically infected cells, releasing bacteria to be destroyed by fresh macrophages.
What does IL-2 produced by Th1 do?
Acts on activated naive CD4 and CD8 cells to alter the balance between Th1 and Tfh to favour Th1 and influences the differentiation of CD8 CTLs and memory CD8 T cells.
What produced by Th1 cells encourages monocyte differentiation and production of monocytes in the bone marrow?
IL-3 and GM-CSF
What does TNF-alpha and LT-alpha produced by Th1 cells do?
Activates endothelium to induce monocyte binding and exit from blood vessels at site of infection.
What does Th1 producing the chemoattractant CCL2 do?
Causes macrophages to accumulate at the site of infection.
What does Th2 produce to induce epithelial cell repair and mucus and what does this lead to?
IL-13
Leads to increased cell turn over and movement to help shedding of parasite.
Mucus helps prevent adherence and accelerates the loss of the helminth.
what is produced by Th2 cells to increase smooth muscle contraction to enhance worm expulsion?
IL-13
What does IL-13 and IL-4 do to macrophages after being produced by Th2?
Produce arginase-1 expressed by M2 macrophages to increase smooth muscle contraction and enhance tissue remodeling and repair.
What does IL-5 produced by Th2 cells do?
Recruits and activates eosinophils which produce MBP which kills parasite. They can also mediate ADCC using parasite specific Ig.
What does Th2 drive mast cell recruitment via and what does this do?
IL-3, IL-9 and specific IgE arms mast cells against helminths by producing things such as histamine, TNF-alpha and MMCP. These recruit inflammatory cells and remodel the mucosa.
What does IL-17 and IL-22 produced by the Th17 cells do?
induce the production of antimicrobial peptides by epithelial cells to kill of inhibit the growth of bacteria attached to the epithelial.
What would happen to the epithelial cells if Th17 only produced IL-22?
Increase epithelial cell turnover as shedding impairs bacterial colonization.
What can only IL-17 produced by the Th17 cells do?
Activate stormal cells, myeloid cells and endothelial cells to produce chemokines or G-CSF.
Chemokines recruit neutrophils
G-CSF - stimulates neutrophil production in the bone marrow which increases the number or neutrophils circuting and at the site of infection.
What chemoattractant is produced by Th17 to increase other Th17 cells at the site of infection?
CCL20
What are CD8 t cells important in protection against?
Virus, intracellular bacteria and tumours.
What must CD8 T cells be able to kill?
Any cell infected with a virus even if there is no co-stimulatory molecules
What can enhance CD8 T cells?
CD4 T cells to recognise the antigens and secrete IL-2 to increase the activation of CD8 T cells.
How do CD8 T-cells kill?
CTL recognises and bind to virus infected cells. CTL programs target for death inducing DNA fragmentation and then migrates onto new target. The original target then dies by apoptosis but the neighbouring cell is not killed.
What are the two ways Cytotoxic/ killer T cells kill?
1) Perforin/ granzymes
2) Fas/FasL mediated cell killing
How do perforins and granzymes kill cells?
After identifying an infected cell cytotoxic T cells release perforins to create pores that induce the uptake of granzymes into the endosome of the target cell and releases into the cytosol activating caspase so the cell undergoes apoptosis.
How does Fas/FasL mediated cell killing work?
FasL is found on he CTL and can interact with Fas on target cell causing apoptosis
Can cancer cells be killed by CTL (cytotoxic T lymphocytes)?
Yes
