Regulatory T-cells Flashcards
Why is there a need for immune regulation?
The balance between fighting infection and leaving uninfected tissue alone can become unbalanced
This can lead to:
- Autoimmunity - immune destruction of normal tissues
Immunopathology - damage to normal tissue following an immune response to infection
What are the different receptors expressed on thymus derived regulatory T cells that distinguish them from conventional T cells?
CD25 - subunit of IL-2
FOXP3 - transcription factor (distinguishing factor)
CTLA4 - delivers negative signal to T cells
What are the main methods of action of Treg?
Production of immunosuppressive cytokines:
- IL-10
- IL-35
Direct killing:
- Granzymes A and B get into Teffector cell through perforin pores
Metabolic disruption:
- Adenosine binds to A2aR on effector cells - eliciting anti-proliferative and anti-inflammatory effects
- Generated by hypoxic cells or through the action of ectoenzymes
Competition:
- Consuming IL-2, a crucial growth factor for effector T cells
Cell contact - dependent suppression - via APCs
- Occupy APC binding sites
- limiting the resources and activation signals available to other T cells, suppressing their proliferation and activity
What is the role of Treg in tissue repair?
Suppress inflammation and autoimmunity
Production of growth factors
What are some potential detrimental effects of Treg?
Cancer:
- Tumours are similar to normal tissue and represent sites of chronic inflammation
- Hypothesise that immune responses to tumours are suppressed by Treg
- Treg frequencies are increased in many different human cancers
- Treg inhibit anti-tumour T cell responses
What are some treatment options to deplete Tregs in patients with cancer?
Targeting inhibitory receptors
- PD-1 and CTLA4 more highly expressed on Tregs
- Targeting CD25 - more highly expressed on Tregs
Cyclophosphamide
- Breakdown products target rapidly dividing cells
- Used at high doses to kill cancer cells (chemotherapy)
- Used at low doses to selectively kill Tregs (immunotherapy)
How can T cells be exploited for therapeutic purposes?
Suppress (increase Treg activity)
- Allergy/asthma (exposure to low dose soluble antigen may induce Tregs)
- Immune responses to transplants (infusion of Tregs may prevent rejection of transplant)
Boost (decrease Treg activity)
- Immune responses to cancer
- Improve vaccine efficacy
Why are Tregs described as plastic
Can alter characteristics based on environmental cues
- Cytokines
- Strength of signal (through the TCR and other co-stimulatory/co-inhibitory molecules)
- The nature of the microenvironment
What are some examples of alterations to Treg and what causes them?
Production of inflammatory cytokines, retain suppressor function
Production of inflammatory cytokines, loss of suppressor function “fragile Treg”
Loss of Foxp3, production of inflammatory cytokines, loss of suppressor function “ex-Treg”
Cause:
- Transcriptional regulation
- Epigenetic regulation
- Metabolic programming
