L15- CD4+ Regulatory T cells

Question 1

What is the consequence of immune overreaction to an internal threat?

Answer 1

Autoimmunity

Question 2

What is the consequence of immune overreaction to an external threat?

Answer 2

Allergic reaction

Question 3

What is the consequence of immune underreaction to an internal threat?

Answer 3

Cancer

Question 4

What is the consequence of immune underreaction to an external threat?

Answer 4

Infection

Question 5

Why must immune homeostasis be maintained?

Answer 5

Immunity provides clearance of infection (viruses, bacteria) and tumour eradication. But in excess it can cause chronic inflammation, allergy and autoimmune disease.

Question 6

What is central tolerance?

Answer 6

(Negative selection)

The process of eliminating any developing T or B lymphocytes that are reactive to self

Question 7

How does the thymus carry out central tolerance?

Answer 7

• 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.

Question 8

What are human CD4+ CD25+ T cells?

Answer 8

• 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

Question 9

What diseases are caused by the defective function of CD4+CD25+ T cells?

Answer 9

• Rheumatoid arthritis
• Type 1 Diabetes Mellitus
• Multiple sclerosis
• Allergy

Question 10

What are regulatory T cells markers other than CD25+?

Answer 10

• CTLA-4
• GITR
• LAG-3
• FR4

None of these appear fully exclusive

Question 11

What is Foxp3?

Answer 11

X-chromosome encoded gene for forkhead helix domain of scurfin protein

Question 12

What does Foxp3 do?

Answer 12

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

Question 13

How does Foxp3 work?

Answer 13

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

Question 14

Is Foxp3 an exclusive Treg marker in mice?

Answer 14

Yes- only expressed by CD4+CD25+ T cells

Question 15

Is Foxp3 an exclusive Treg marker in humans?

Answer 15

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

Question 16

What is the mechanism of action of CD4+CD25+ Tregs?

Answer 16

1. Inhibitory cytokines released to impact effector T cells e.g TGFbeta, IL10, IL35
2. Cytolysis of effector T cells using granzyme A/B
3. Metabolic disruption- competing directly with effector T cells for IL12 which leads to death due to cytokine deprivation
4. Targeting dendritic cells- inhibition of maturation and function via CTLA4/LAG3

Question 17

What are the targets of CD4+CD25+ Tregs?

Answer 17

• 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

Question 18

What are natural Tregs?

Answer 18

Generated in the thymus

Question 19

What are pTregs and iTregs?

Answer 19

Peripherally generated

Question 20

What are the types of inducible Tregs and how are they generated?

Answer 20

TH3 cell- induced by TGFbeta, produce TGFbeta

TR1 cell- induced by IL10 and produce mainly IL10, do not constitutively express Foxp3

Question 21

What does IL10 do?

Answer 21

• Inhibits T cell proliferation

* Inhibits APC function (less MHC2)

Question 22

What does TGFbeta do?

Answer 22

• Inhibits T cell proliferation and effector function
• Inhibits B cell proliferation
• IgA isotype switch
• Inhibits macrophages
* But also has proliferative effects

Question 23

What are therapies targeting Tregs?

Answer 23

• Induction of tolerance in transplantation or autoimmunity

* Reducing immunoregulation in cancer

Question 24

How can Treg function be decreased?

Answer 24

• Removal of nTregs
• Blockage of nTreg effector molecules (IL10, TGFbeta, CTLA-4)
• Enhancement of effector T cells function

Question 25

How can Treg function be increased?

Answer 25

• nTreg transfer
• Polyclonal stimulation
• Enhancement of nTreg function (TGFbeta, IL-2)