3. Peripheral CD4+ T cell differentiation Flashcards
How quickly can T cells expand?
They can go from 200 naive cells to 10,000 effector cells in 4 days.
Overview of clonal T cell expansion
- Naive T cell expressing a single TCR on the surface
- Interaction with an APC expressing an MHC.
- If the TCR and MHC interact in a stimulatory way it will activate the T cell.
- Naive T cell receives a signal to expand and differentiate
Why is differentiation of CD4 T cells also important?
- It tailors effector mechanisms to pathogens.
- Limiting collateral damage and keeping the response just enough.
- It supports immunological memory and makes vaccination possible
- Together, these all optimise the adaptive immune response.
How were the different types of CD4 cells originally characterised?
A 1986 publication at the point it became possible to clone enough CD4 cells in culture to identify the proteins in them.
The CD4 T cells were classified by what they produce.
Showed that different cytokines are made depending on differentiation and function.
Have all the CD4+ subtypes been discovered?
No, more are still being found
Why is correct differentiation of CD4 T cells important?
- The type of CD4 response can determine the outcome of infection.
- Th1 responses can clear and control certain infections, whereas Th2 responses won’t.
- This changes the infection outcomes eg death.
- Due to genetics not everyone has the same ability to make the different responses.
What are naive CD4 T cells?
Multipotent
Does the peptide presented to the T cell determine its differentiation fate?
No. At this point the T cell is still multipotent and what activates the T cell doesn’t determine its fate.
However, the affinity at which this activation occurs does have some bearing on the fate of the cell.
Does the environment the T cell is in determine its differentiation fate?
Yes, it plays a role through the cytokines in the environment but there are also other factors.
What factors can determine a CD4 T cells fate?
- APC phenotype - how the antigen is presented
- Concentration of antigen
- TCR activity
- Genetics
- Cytokine signalling
- Adjuvant immunity, e.g. TLR signalling and innate immunity
What 3 signals are needed for T cell activation?
- TCR- MHC recognition
- Costimulation
- Instruction through cytokines
Where does CD4 T cell differentiation occur?
In the lymph nodes but in different areas for different cell types
Th1 differentiation in the lymph node
- Dendritic cell 1 generates peripheral cells deep in the T cell zone.
- This produces effector Th1 cells and T follicular helper cells.
- The Tfh aid specific antibody production.
- This is the type 1 response and mostly for intracellular pathogens.
Th2 differentiation in the lymph nodes
- Dendritic cell 2 generates Th2 effector cells adjacent to the B cell follicles.
- Also, some generation of Tfh cells.
What initiates Tfh differentiation?
Lymph node resident cDC2
Differentiation signals: Th1
IL12
Differentiation signals: Th2
IL4
Differentiation signals: Th17
IL6, TGFß and IL23
Differentiation signals: Tfh
IL21
Differentiation signals: Treg
IL21
Effector Molecules: Th1
IFNy
Effector Molecules: Th2
IL4, IL5, IL13