L15- CD4+ Regulatory T cells Flashcards
What is the consequence of immune overreaction to an internal threat?
Autoimmunity
What is the consequence of immune overreaction to an external threat?
Allergic reaction
What is the consequence of immune underreaction to an internal threat?
Cancer
What is the consequence of immune underreaction to an external threat?
Infection
Why must immune homeostasis be maintained?
Immunity provides clearance of infection (viruses, bacteria) and tumour eradication. But in excess it can cause chronic inflammation, allergy and autoimmune disease.
What is central tolerance?
(Negative selection)
The process of eliminating any developing T or B lymphocytes that are reactive to self
How does the thymus carry out central tolerance?
- Positive selection of CD4+ (and CD8+) T cells which recognise antigens on self MHC molecules.
- Negative selection of CD4+ (and CD8+) T cells that recognise self peptides on MHC molecules with an affinity that is too high.
- End result: T cell repertoire that interacts with self MHC but does not respond to self peptides.
What are human CD4+ CD25+ T cells?
- 2%-10% of peripheral CD4+ T cells
- Regulatory T cells
- Present in blood, lymphoid organs, tissues
- CD4+CD25+ T cells with high expression of CD25+ are the most common
- Maintain immune tolerance to self, dietary and foreign proteins
What diseases are caused by the defective function of CD4+CD25+ T cells?
- Rheumatoid arthritis
- Type 1 Diabetes Mellitus
- Multiple sclerosis
- Allergy
What are regulatory T cells markers other than CD25+?
- CTLA-4
- GITR
- LAG-3
- FR4
None of these appear fully exclusive
What is Foxp3?
X-chromosome encoded gene for forkhead helix domain of scurfin protein
What does Foxp3 do?
Master regulator for CD4+CD25+ T regulatory cells
Overexpression of Foxp3 in CD4+CD25+ in T cells induces the Treg phenotype and function
Mutations in Foxp3 leads to scrufy in mice and IPEX in humans
How does Foxp3 work?
Binds DNA, localises to the nucleus and can act as a transcriptional repressor as well as activator.
It may stabilise and positively feedback on its own expression and also through repression of alternative differentiation pathways
Binds NFAT
Is Foxp3 an exclusive Treg marker in mice?
Yes- only expressed by CD4+CD25+ T cells
Is Foxp3 an exclusive Treg marker in humans?
Foxp3 is expressed by CD4+CD25+ (high) T cells
Foxp3 T reg phenotype also induced in non-reg CD4+ T cells by:
• Cytokines (TGFbeta, IFNgamma)
• T cell activation
What is the mechanism of action of CD4+CD25+ Tregs?
- Inhibitory cytokines released to impact effector T cells e.g TGFbeta, IL10, IL35
- Cytolysis of effector T cells using granzyme A/B
- Metabolic disruption- competing directly with effector T cells for IL12 which leads to death due to cytokine deprivation
- Targeting dendritic cells- inhibition of maturation and function via CTLA4/LAG3
What are the targets of CD4+CD25+ Tregs?
- CD4+ T cells- proliferation, cytokine production
- CD8+ T cells- proliferation, cytokine production, cytotoxicity
- B cells- antibody production
- NK cells- proliferation, cytokine production, cytotoxicity
- APC- T cell stimulatory capacity, cytokine production
What are natural Tregs?
Generated in the thymus
What are pTregs and iTregs?
Peripherally generated
What are the types of inducible Tregs and how are they generated?
TH3 cell- induced by TGFbeta, produce TGFbeta
TR1 cell- induced by IL10 and produce mainly IL10, do not constitutively express Foxp3
What does IL10 do?
- Inhibits T cell proliferation
* Inhibits APC function (less MHC2)
What does TGFbeta do?
• Inhibits T cell proliferation and effector function • Inhibits B cell proliferation • IgA isotype switch • Inhibits macrophages * But also has proliferative effects
What are therapies targeting Tregs?
- Induction of tolerance in transplantation or autoimmunity
* Reducing immunoregulation in cancer
How can Treg function be decreased?
- Removal of nTregs
- Blockage of nTreg effector molecules (IL10, TGFbeta, CTLA-4)
- Enhancement of effector T cells function
