T cell regulation Flashcards
AIRE and Tregs
AIRE supports the generation of Tregs against some of the self-antigens.
Scurfy mice
They have a loss of function mutation of FoxP3. They develop fatal autoimmunity and die very early, and they have very large lymph nodes. They showed that FoxP3 is an essential immunoregulator (Brunkow et al. 2001)
IPEX syndrome
A rare disorder caused by mutations in the FoxP3 gene, defects of Treg function and strong autoimmunity
FoxP3
- Transcription factor
- Expressed by Tregs
- Essential immunoregulator
- Scurfy mice which have loss of function mutation of FoxP3 die very early due to severe autoimmunity
- Suppresses production of IL-2, IL-4 and IFN-y (Hori et al. 2003)
Which T cells are selected to become Tregs in the thymus?
Stronger affinity to self MHC than the selected effector T cells but weaker than the ones deleted via negative selection. ‘strong but not too strong’
- Cells with stronger affinity to self MHC which can upregulate FoxP3 and cells which can upregulate CD25 can avoid negative selection and become regulatory T cells
- CD25 is an IL2 receptor and through IL2 it can upregulate expression of FoxP3 (Lio et al. 2008)
Nr4a
- Transcription factors which can promote FoxP3 expression when moderate TCR signal
- If there is a large accumulation of them, it leads to apoptosis (negative selection) when high TCR signal
What happens if you delete Nr4a receptors?
No Tregs
peripheral Tregs
When T cells with weaker signal to self-antigen will become activated in the periphery without co-stimulation by inflammatory cytokines they will start upregulating FoxP3. This usually happens in the gut, where is a lot of TGF-B and retinoic acid
TR1 cells
- Do not express FoxP3
- Produced by repetitive stimulation of T cells in the presence of IL-10 and IL-27
Tfr cells
T follicular regulatory cells
- They regulate germinal centre responses
- Expresses CXCR5 to migrate to germinal centres
- Express FoxP3
Treg function
- FoxP3 stops their own expression of IL-2 and IFN-y so it stops themselves from being autoreactive
- Production of inhibitory cytokines (IL-10, TGF-B, IL-35) TGF-B is also found on the membrane of Tregs so that they can also deliver it through cell to cell contact not only by secreting it
- They make perforin and granzymes to directly kill cells for example APCs
- They express CD25, which is a high affinity receptor for IL-2 so they will uptake IL-2 from the environment and IL-2 is important for proliferation of conventional T cells so it will stop that
- They have CD39 and CD73 which break down ATP into adenosine
- They inhibit DCs by:
1) CTLA-4 which has higher affinity to CD80/CD86 than CD28 does and it rips off CD80/86 from DCs so that they cannot provide co-stimulatory signals
2) They express LAG3, which binds to MHC class II
3) Making DCs to inhibit other cells
Treg suppression assay
You label cells with CFSE dye and if the cell population is inhibitory then you will get less T cell proliferation and less dye expression
