T cell effector functions Flashcards
Describe the homing of effector T cells to sites of infection
After completing differentiation in the lymph node, dendritic cell nursery
Clones of effector CD8 T cells and effector CD4 Th cells leave the secondary lymph tissue, enter circulation and seek out sites of infection/antigen
The naïve T cells upon differentiation into effector T cells, have changed their cell surface molecules that allow them to home into sites of infection
T cells encounter antigen in the peripheral tissues and there they also require antigen-specific conjugate pairing with the target cell (that have intracellular pathogens)
The effector T cells connect at the synapse and deliver their effector molecules to the target cell to mount a response
Describe the role of cytokines and cytotoxins for effector T cell function
Cytotoxins kill target cells, released only by effector CD8 cytotoxic T cells
Cytokines alter the behaviour of the target cell (all effector T cells make cytokines)
Cytokines perpetuate & enhance the immune response in that area by binding to cytokine receptors (cell-surface)
The intracellular signals generated by these interactions induce changes in gene expression within the target cell
Describe the function of cytotoxic CD8 effector T cells at sites of infection
Describe the function of effector CD4 helper T cell subsets (Th1, Th2, Th17, Tfh and Treg) at sites of infection/injury
Give 2 examples of differences in cell surface molecules between naïve and effector T cells
Naïve T cells express L selectin, not VLA-4
Naïve T cells express CD45RA, not CD45R0
All effector T cells leave secondary lymph tissues, enter circulation and seek out sites of infection
True or False
False, CD4 Tfh cells move to the B cell zone to activate a B cell response (don’t leave the lymph node)
Which cell surface receptors do naïve T cells have?
Unique TCR, CD4 or CD8, L-selectin, LFA-1, CD2, CD44, CD45RA
Which integrin is upregulated on effector T cells for homing to inflamed tissue?
VLA-4
What is the adhesion molecule that is activated on the endothelial cells of inflamed target cells and is primed for the recognition of VLA-4 on effector T cells?
VCAM-1
Which interaction allows the effector T cells to leave the blood stream and enter the inflamed tissue? How?
VLA-4 & VCAM-1 interaction halts the passing effector T cells and directs them to the infected tissue
Which cell surface molecules are expressed in both naïve and effector T cells, but are expressed far more in effector T cells than naïve T cells
CD2 and LFA1 (expressed 2-4 times more)
When TCR engages with antigen presented by the T cell, what happens to other cell surface molecules?
The TCR engagement with the antigen presented by the target cell, induces LFA-1 to go through a conformational change that allows it to have a more long-lived interaction with ICAM-1
Why is effector T cell activation less strict than naïve T cell activation?
Effector T cell activation requirement is less strict than the activation of naïve T cells as co-stimulation (CD28 and B7) is not needed for T cell recognition of antigen at the infection site
This means that T cells are now able to kill any type of cell that becomes infected with a virus
How do effector T cells exert their functions?
Conjugate pair with target cell
Localised area of contact between the two cells
T cell synapse formed, where the T cell receptor and the co-receptor bind the MHC molecule and peptide complex
At this synapse, the effector molecules made by the T cell are delivered to the target cell
These are the cytokines and the cytotoxins
5 min contact time required for the synapse to form and the enzymes to be dropped
What is the difference between cytokines and cytotoxins, in terms of their production style
Cytokines are made only after the effector T cell has made a conjugate pair with the target cell
Then upon demand, they are delivered to the target cell
They are never made and stored in the CD4 T cell for future use
However, the cytotoxins are manufactured and stored in lytic granules before and encounter with the target cell
The killing mechanism of CTLs are similar to which cell type?
NK cells
What are the cytotoxins that CD8 T cells release & brief descriptions of them:
Granzymes (family of serine proteases)
Perforin (membrane disrupting protein)
Serglycin (proteoglycan which interferes with glycan structures)
All of the above make pores in the target cell
Granulysin (is a detergent like protein that associates with membranes and dissolves them)
All are very potent, dropped right at the point of contact
CD8 T cells kill which cells
cells overwhelmed by intracellular infections
The infected cells are sacrificed
killing is targeted, upon recognition, the CTLs contact, polarise and release the lytic granules
Another mechanism by which the CTLs kill target cells:
CTLs express Fas-L
which binds the death inducing Fas-R on the target cells
This induces apoptosis, without granules
Plays a minor role in killing by CD8+ CTLs
How do CD8 T cells kill many, many cells
As target cell starts to die, CTL is released and starts to make new granules (regenerate their granules)
Once new granules have been made, CTL is able to kill another target cell
Which IFN is secreted by CD8 T cells and why
CTLs also secrete IFN-γ to inhibit viral replication and increases viral antigen processing
IFN-γ also activates macrophages to dispose of dying cells
Role of Th1 cells
Help macrophages to be more efficient and proficient
Th1 cells are stimulated by which cytokines? Which is made by which cells?
NK cells pump out IFN gamma, which then stimulates the dendritic cells and the macrophages to make IL-12, which then stimulates the Th1 cells that helps to make the macrophages be more efficient (positive feedback loop that amplifies the immune response)
Which transcription factor is characteristic of the Th1 cells?
T-bet
What do Th1 cells produce and how do they act?
They produce IFN-gamma, which activates macrophages to be more proficient killers by increasing their synthesis of microbicidal agents such as NO, ROS (reactive oxygen species and proteases)
This is the classical pathway of macrophage activation and the IFN-gamma secreted by CD8 CTL can also activate the macrophages
How do effector Th1 CD4 cells induce macrophage activation?
Th1 cell arriving at site of infection encounters resident macrophages presenting antigen on MHC-II
Th1 cell and macrophage make a cognate pair… 2 signals activate the macrophage:
IFN-γ binds receptor on macrophage
CD40 ligand on Th1 cell binds CD40 receptor on macrophage
Ensures appropriate focus of immune response & this enables the macrophage to upregulate its production of toxic substances to deal with the infection
What is the role of Th2 cells?
Th2 cells defend against parasites (multicellular and large pathogens)
What is the role of Th2 cells?
Th2 cells defend against parasites (multicellular and large pathogens)
What are Th2 cells stimulated by?
IL-4 which mast cells, eosinophils produce in the area where the parasites are
What is the transcription factor that defines the Th2 cells?
GATA-3
What do Th2 cells release in response?
They promote IgE mast cell and eosinophil mediated destruction of parasites
(positive feedback –> eosinophils release IL4, which stimulates Th2 cells. Th2 cells make IL4 which is super important in promoting B cells to produce IgE antibodies that work on mast cell degranulation)
IgE coats helminths marking them for destruction by eosinophils
IgE binds to surface of mast cells (Fc), and binds to the helminth antigen (Fab)
Crosslinking results in degranulation of those cells
Parasites too large for phagocytosis –> need a potent, local response
What do Th2 cells to macrophages?
Work opposite to the Th1 cells classic macrophage activation
These cells are involved in alternative macrophage activation and they inhibit the classical macrophage activation pathway
This is because the toxic microbicidal substances produced by the activated macrophages (M1) are damaging to the host tissue
Th2 cells release IL4 and IL13 which inhibit the classical macrophage activation and instead they work on M2 macrophages to secrete IL10 & TGF-beta that act on fibroblasts, to promote tissue repair, ant inflammatory effects, wound repair, fibrosis
The potent response to the parasites, causes lots of local damage
hence, the Th2 cells also help heal
Th2 cells are making more of the IL4 that starts their differentiation process
Th1 cells are making more of the INF-y that activate macrophages, which produce more IL12, which stimulate the differentiation of Th1 cells
These positive feedback loops are called
Polarisation = perpetuating that particular type of response
What are Th17 cells stimulated by
Extra-cellular bacteria & fungi
which is presented by the activated APCs (MHC class II) they produce particular cytokines
which cause the differentiation of the Th17 cell
Which transcription factor defines the Th17 cells?
Th17 cell is defined by ROR-gamma-t transcription factor
What do the Th17 cells do and secrete?
Stimulate the recruitment of neutrophils
they secrete IL17 and IL22 which stimulates the production of CXCL8 (IL8) (chemoattractant for neutrophils) and the recruitment of neutrophils
Th17 cells induce inflammation that accompanies many T cell-mediated adaptive immune responses
IL17 and IL22 stimulate epithelial cells, which are stimulated to make antimicrobial peptides to improve the integrity of their barriers and promote the repair of damaged epithelia
Function of Tfh cells
Stay behind in the lymph node, and function to help B cells make antibody
They draw out the B cells, tht have been stimulated in the B cell zone of the lymph node, and then combine with them to form an extrafollicular focus
They provide B cells the stimulation they need to finish their maturation and become antibody making machines
Which chemokine receptor draws Tfh cells close to B cells?
CXCR5
Tfh and Naive B cells, recognise different epitopes of the same antigen… how?
Naïve B cells bind antigen in the B cell zones of the lymph node, with surface Ig (BCR) - antigen is internalised, processed in endocytic vesicles
Antigen presented on B cell MHC class II for recognition by Tfh cell = linked recognition
The Tfh cell recognises a peptide, derived from the B cell’s antigen via MHC class II … then what?
Tfh cell and MHC class II interaction
then
Cognate interaction leads to expression and recognition of CD40L ligand on Tfh cell by CD40 on B cell
Triggers IL-4, IL-5 and IL-6 production by the Tfh cell which bind to the cytokine receptors on naive B cell
That causes B cell activation and differentiation into plasma cell
Cytokines produced by Tfh cells help determine heavy chain isotype produced (isotype switching)
which transcription factor characterises Treg cells?
FoxP3
What do the Treg cells do?
They suppress the activation of harmful lymphocytes
They wind down the immune response once the pathogen is cleared
They limit tissue damage
Where are Treg cells developed?
Treg cells commit during thymic development or in the peripheral lymph nodes when they recognise self-antigen
The Treg cells emerge during infection and secrete anti-inflammatory cytokines
How do T reg cells suppress the immune responses? By which cytokines and cell surface receptors
By the production of the immunosuppressive cytokines IL10 and TGF beta which inhibit the activation of lymphocytes, DCs, and macrophages
They also express CTLA-4 which block/removes B7 molecules on the antigen presenting cells, and makes them incapable of providing stimulation to the T cells via CD28
CTLA-4 binds B7 20 times more strongly than CD28
CTLA-4 is induced in activated T cells, so they aren’t switched on forever
It functions as a break, to inhibit the activation and proliferation of T cells (off-switch)
They also express high levels of IL2R which outcompetes for the IL2 (that is a T cell growth factor). This reduces the availability of IL2 for other T cells
A fraction of antigen-activated T cells differentiate into…
long-lived memory cells which survive after infection is eradicated and antigen is no longer present
memory cells are rapidly induced to act upon the antigen they encounter & recognise
after re-activation, they respond much more vigorously and rapidly than naïve cells
Where are central memory cells located?
in lymphoid organs - responsible for rapid, clonal expansion after re-exposure to antigen
Where are effector memory cells located?
in mucosal, and peripheral tissues
mediate rapid effector functions on the reintroduction of antigen to these sites
Changes in the proportions of naïve and memory T cells with age
Frequency of memory cells increases with age
Accumulation of memory cells compensates for reduced output of new, naïve T cells
Thymus involutes after puberty
Summary of the actions of the effector T helper cells
Th1 - macrophage activation
Th2 - eosinophil & mast cell activation against parasites, and alternative macrophage activation
Th17 - neutrophil activation and recruitment to skin and gut mucosa
Tfh - antibody production, isotype switching (recognise different epitopes of the same antigen)
Treg - suppress the immune response by limiting the activities of the effector T cells
Summarise the defining cytokines for the Th cells
Th1 - IFN gamma and IL12 Th2 - IL4, IL5, and IL13 Th17 - IL17 and IL22 Tfh - IL6, IL21, IFN gamma, IL4 Treg - IL10, TGF beta,
