March 31st (Exam 3) Flashcards
Because negative selection is not always perfect, what processes do T-cell have in place so that T-cells that sneak out of the thymus and encounter a self-antigen, don’t wreak havoc on the body?
When those naive T-cells who sneak out of the thymus encounter antigen, it will almost always be on cells that CANNOT and DO NOT express the costimulatory molecule B7, which is required for full activation.
What do these T-cell become once they interact with their antigen on a cell that does not have B7?
They become permanently anergic.
What is the defining characteristic of anergic T-cells?
Why?
Think about the really important duties that the co-stimulatory molecule - co-stimulatory receptor signal had…
They cannot make IL-2 or make the TFs for IL-2 because even if they find their co-stimulatory molecule on an APC they are already anergic.
IL-2 is required to sustain T-cell growth and differentiation.
When immunologists were unaware of anergy, they became puzzled with the fact that immunizing animals with pure proteins hardly ever led to an adaptive response.
But they saw that when they added bacteria or the bacterial products they did get one.
Why?
The bacterial contaminants initiated an innate immune response that induced the expression of the co-stimulatory molecules in DCs!
What do you call something that enhances the adaptive immune response to antigens?
An adjuvant
The differentiation of T-cells into their different types depends upon what?
- The tissue of origin of the DCs that activated the T-cells
- The nature of the pathogen
- The innate immune response
How many types of CD4 T-cells are there?
What types of cells do they interact with?
5
They interact with:
- Phagocytes (neutrophils/mac/DC)
- Granulocytes (
- Lymphocytes - (B/T cells)
Name the five types of CD4 T-cells and briefly explain their functions.
- T (h) 1 - they activate macrophages
- T (h) 17 - they enhance the neutrophil response
- T (h) 2 - they activate the cellular and antibody response to parasites
- T(FH) - activate B cell maturation of antibody response
- T(reg) - suppress other T effector cells
What do we call the transcription factor that determines the differentiation pathway?
The master regulator
What is a polarized T-cell response?
A polarized T-cell response occurs when an activated T cell differentiates into a specific type (e.g., Th1 or Th2) and produces cytokines that encourage more T cells to become the same type. This creates a positive feedback loop, amplifying the response and cytokine production of that specific T cell type.
Polarized T-cell responses guide the immune system toward either cell-mediated immunity or humoral immunity.
Which T cell corresponds to each type of immunity?
What does each type of immunity mean?
T (h) 1 cells correspond to cell mediated immunity - the response is dominated by the effector cells of the immune system.
T (h) 2 cells correspond to humoral immunity - the response is dominated by antibodies.
Which type of T-cells (CD4 or CD8) are more functionally diverse?
Which interacts with a wider range of target cells?
Why?
CD4 cells are
CD8 cells interact with a wider range of target cells because pretty much all cells can become infected with intracellular viruses.
Why does CD8 T cell activation require stronger co-stimulatory signals than CD4 T cells?
Because Cytotoxic T cells (CD8) are very destructive and inflict damage on any target tissue to which they are directed - this is only good when those cells are infected with pathogen.
Explain the two different ways in which CD8 T cells are activated.
(Simple and not so simple way)
What is required for a CD8 T cell proliferation and differentiation?
The first way (just as you would think) involves a dendritic cell that is infected with a certain type of virus providing the sufficient signals through its MHC Class I molecule:peptide and costimulatory molecule to activate the CD8 T cell to effector status. The T cell then releases IL-2 driving its proliferation and differentiation in a autocrine fashion.
The other way, when dendritic cells are infected with other types of viruses, involve more complex signalling pathways. The dendritic cell must interact with both the CD8 viral antigen specific naive T cell and another virus-specific CD4 T cell. The signal between the CD4 T cell and the dendritic cell provides the necessary boost of IL-2 secretion that acts on the CD8 T cell to allow its proliferation and differentiation.
Now that we have our effector T cells, where do they go?
How do they get there?
They need to move to the infected tissue.
During their differentiation, from naive to effector T-cells, changes in the cell surface molecules make this travel possible.
Explain these changes in cell surface molecules simply.
They get more adhesion molecules so that they can find their antigen, attach and do whatever they are meant to do.
Why is it important that co-stimulatory signals are not needed to activate the effector functions of effector T cells?
Because it means that the CD8 cells can kill any type of cell that is infected with a virus.
CD4 T-cells are also able to recognize antigen on all cells that express MHC Class II molecules (some cells can be induced to express them via IFN-gamma).
What are the various types of molecules that mediate T-cell effector functions?
Explain how they work briefly
- Cytokines - these alter the behavior of cells (change expression) and they are only made by the effector T-cells AFTER a cognate pair has been made with the target cell.
- Cytotoxins - these kill the target cells and are made by CD8 cytotoxic T cells and stored in lytic vesicles BEFORE the interaction with the target cell.
What do cytokines do to a target cell?
Explain what the typical cytokine receptor looks like.
They change the patterns of gene expression in the target cells.
Many of the cytokine receptors are two membrane proteins that only come together when in presence of the cytokine and interact with cytoplasmic kinases - signal transduction.
What do we call the inactive form of protein kinases?
What do they phosphorylate once they are active?
What are they?
The Janus kinases (JAKs) and once they become active they phosphorylate STATs
STATs are Signal Transducers and Activators of Transcription - these are proteins that become phosphorylated by active kinases.
Explain the basic pathway of a cytokine acting on a cytokine receptor that results in changes in gene expression.
Explain the basic structure of all things involved and what happens.
When a cytokine associates with a cytokine receptor single units (not yet dimerized) that are each bound to a JAK (inactive kinase) they will form the receptor which then gets phosphorylated by the now active kinases.
Then the STATs bind to the receptor and are themselves phosphorylated, causing them to dimerize and move to the nucleus to initiate gene expression.
How is the the whole cytokine to changes in gene expression regulated?
- Phosphatases - they do what you would think
- SOCS (Suppressors Of Cytokine Signalling) - these will bind to phosphorylated residues to prevent signalling.
How do the effector functions of CD8 T cells work?
How do they not kill off cells that aren’t infected with virus?
As said before, after their initial antigen activation and differentiation, they make the cytotoxins and pack them in lytic vesicles, traveling to the infected tissue.
The release of these cytotoxins is concentrated and dependent upon antigen specificity - in other words - the CD8 T cell will only release the lytic granules when they find their viral-antigen on MHC Class I molecules of infected cells. They leave the healthy cells alone.
How do CD8 T cells kill the infected cells?
Apoptosis
