March 28th (Exam 3) Flashcards
What is the process by which a naive T cell divides, proliferates, and differentiates into an effector T cell following encounter with antigen?
This is called T-cell priming or T cell activation.
What stage of the primary adaptive immune response is T-cell priming?
This is the first step.
What do CD8 T cells become and what do they do?
What do CD4 T cells become and what do they do?
Cytotoxic T cells that kill pathogen-infected target cells.
We collectively call the CD4 T cells the helper cells, but they actually have five different functional subtypes - they ALL release cytokines.
What are the two ways in which a professional antigen presenting cell (DC) takes up extracellular material for peptide processing and loading on MHC Class II molecules?
- Micropinocytosis (aka receptor-mediated endocytosis) - this is when specific receptors are used to capture bacteria and virus particles from the extracellular fluid (small volumes)
- Macropinocytosis - this is the nonspecific ingestion of larger volumes of fluid (used to capture stuff that is not recognized by a receptor)
What are the three ways in which a professional antigen presenting cell (DC) takes pathogen material (from a variety of sources) processes the peptides, and loads them on to MHC Class I molecules?
- Viral infection (intracellularly) this is just the typical way that MHC Class I molecules are loaded. The peptides are broken down within the cytosol and brought into the ER where they are loaded.
- DC transfer (when they are too sick) - When DCs become too sick to activate T cells, they can transfer/infect the viral material to another DC that is resident to the lymph which then takes up the processed peptides in a vesicle and presents it on MHC Class I molecules
- Cross presentation - this is when viral material is taken up from outside the cell (extracellular vesicle) and is somehow incorporated into the exocytic pathway (normal MHC Class I) probably by taking that unprocessed material and dumping it in the cytosol.
Does the immune system initiate an adaptive immune response at the infection site?
If yes, explain how if not, what do they do instead?
Simplify the DCs role.
The strategy is to capture some of the pathogen and get it to the secondary lymphoid tissue.
The Myeloid DCs take up antigen at the site of infection and travel to the secondary lymphoid tissue.
Infections at the these different locations have T cell responses where?
- Skin/Other peripheral tissue?
- Blood infections?
- Mucosal tissue (respiratory, gastro, reproductive)?
- Draining lymph node
- Spleen
- Mucosal secondary lymphoid tissue
DCs that are located in the skin and other peripheral tissues are called?
Immature Dendritic Cells
DCs change in significant ways in their journey from the infected skin/periphery tissue to the lymph node.
What are some examples of these changes?
- Cell surface molecules
- Morphology
- Function
What is responsible, both ultimately and directly, for the changes that the DCs undergo as they move from the periphery to lymph circulation to secondary lymph tissue?
What are the effects of activation?
The pathogens that present for the dendritic cells to take up/process are ultimately responsible for the changes that we see.
* The most direct responsibility, however, falls on the many Toll Like Receptors that are highly sensitive to the presence of all manner of pathogens.*
Signals from these receptors change the gene expression of a DC, in short, effectively activating it.
Effects of Activation:
- Increased efficiency with which antigens are taken up, processed, and presented.
- Expression of CCR7 (chemokine receptor type 7) - this is the receptor for the CCL21 (chemokine ligand 21) that is made in the secondary lymphoid tissue and the signals induced by the interactions of the two cause the DC to leave the lymphatic vessel it is in to enter the draining lymph node following the gradient of CCL21 and CCL19.
- Maturation of DCs - when they reach the lymphoid tissue they can no longer take up and process antigen - instead they make more MHC Class I and II molecules.
What do we call the DCs that have undergone the above changes and are now located in the the secondary lymphoid tissue?
They are called mature DCs or Activated DCs
How do T-cells get into the lymph node?
- From the blood they enter via the High Endothelial Venules (HEV) from the capillaries that surround the lymph node and eventually make their way to the T-cell area aka T-cell zone (outermost cortex of node)
- Afferent Vessel of another lymph node
What happens to T-cell generally speaking when they encounter their specific antigen?
How can we account for the delay of the onset of infection and appearance of a primary adaptive immune response?
What about cells that don’t encounter antigen in the lymph node?
They become activated to proliferate and differentiate.
This proliferation and differentiation takes a few days.
The ones that did not encounter antigen (the vast, vast majority of them) will leave the lymph node via the efferent lymph.
What do we call the process by which a naive T cell leaves the bloodstream and enters the T-cell zone of a lymph node?
What is this guided by?
Who is releasing these chemokines and where are the chemokines located?
Homing
It’s guided by CCL21 and CCL19 (like in neutrophils) chemokine ligands.
Stromal cells and DCs in the T-cell area and they are located on the surface of the endothelial cells.
Walk me through the process of a T cell diapedesis to the lymph node.
L-selectin on the surface of the T-cell binds to GlyCAM-1 on the surface of the HEV - effectively halting the T-cell. The CCR7 receptor then binds to the chemokine CCL21 or CCL19 on the surface of the HEV and activates an integrin LFA-1 that binds tightly to ICAM-1. Eventually, following the chemokine, the T-cell squeezes through the HEV.
Now in the lymph node, how does the T-cell get to the T-cell area?
Explain the various interactions with….?
Why is DC-SIGN special?
The T-cell will bind transiently to DCs as it makes its way through the lymph node.
Important Interactions:
- LFA on T-cell to ICAM-1 on DC (weakish)
- ICAM-3 on T cell to the DC-SIGN
DC-SIGN is special because it is unique to DC cells that have been activated.
During the interactions (transient connections) what else is happening?
What does this lead to?
The T-cell is assessing the MHC complexes on the surface of the DC cells in search for one that fits.
When that special peptide:MHC complex is found, a conformational change is induced in the T cell’s LFA-1 molecules that increases the affinity for the ICAMs, effectively prolonging the cell-to-cell contact.
What do we call the combination of the naive antigen specific T cell and DC when they couple together?
Once this coupling has taken place what is the T-cell signalled to do?
We call them a conjugate or cognate pair.
The T-cell (under the influence of the DC) will proliferate and differentiate to form a clone of effector cells (stuff exists in-between)
Again, what happens to the majority of T-cells that have made it to this T-cell area?
What is their departure controlled by?
What is it?
They don’t find their antigens and they pass from the cortex to the medulla and leave the lymph node in the efferent lymph.
sphingosine 1-phosphate (S1P)
S1P is a lipid that is made by ALL cells
Explain how S1P is used to control the departure of effector T-cells and un-activated T-cells via the efferent lymph.
All T-cells have a receptor for S1P EXCEPT those who are currently being nurtured by a DC
The S1P concentration is the lowest in the T-cell areas and increases in the direction of the medulla and the efferent vessel.
In effect, this gradient guides the effector T-cell and un-activated T-cells to the efferent vessel.
What are the various signals that are required for activation of a naive T-cell by a DC?
Signal 1 - these are the intracellular signals that are generated by the ligation of the T-cell receptor and the co-receptor (either CD4 or CD8) with a specific peptide:MHC Complex
(required but no sufficient)
Signal 2 - costimulatory signal delivered by the co-stimulatory receptor on the T-cell (CD28). CD28 binds to the costimulatory molecule B7 ligand that is present on the DC.
Without the co-stimulatory signal, a T-cell can neither divide nor survive.
What type of cells express co-stimulatory molecules?
When do they express them? How?
APCs
They only express them in the presence of an infection - TLRs signalling and other receptors of innate immunity.
How does the immune system make sure T-cell activation doesn’t get out of control once the T-cell has been activated and the problem is being taken care of?
i.e if CD28 is the gas for the T-cell activation, what is the brakes?
An additional and complementary B7 receptor of CD28 is called CTLA4 and it starts to get expressed once the T cells are activated.
Its structurally similar to CD28 but it binds much easier and has the opposite effect - inhibiting activation and proliferation.
Essentially CTLA4 is a built in self regulator for T-cell activation control.
What is the word we used to describe the localized receptor/ligand binding areas between a T-cell and a DC?
We call this the T-cell synapse
