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Immunology > L15- CD4+ Regulatory T cells > Flashcards

L15- CD4+ Regulatory T cells Flashcards

1
Q

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

A

Autoimmunity

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2
Q

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

A

Allergic reaction

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3
Q

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

A

Cancer

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4
Q

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

A

Infection

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5
Q

Why must immune homeostasis be maintained?

A

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

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6
Q

What is central tolerance?

A

(Negative selection)

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

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7
Q

How does the thymus carry out central tolerance?

A
  • 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.
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8
Q

What are human CD4+ CD25+ T cells?

A
  • 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
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9
Q

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

A
  • Rheumatoid arthritis
  • Type 1 Diabetes Mellitus
  • Multiple sclerosis
  • Allergy
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10
Q

What are regulatory T cells markers other than CD25+?

A
  • CTLA-4
  • GITR
  • LAG-3
  • FR4

None of these appear fully exclusive

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11
Q

What is Foxp3?

A

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

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12
Q

What does Foxp3 do?

A

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

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13
Q

How does Foxp3 work?

A

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

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14
Q

Is Foxp3 an exclusive Treg marker in mice?

A

Yes- only expressed by CD4+CD25+ T cells

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15
Q

Is Foxp3 an exclusive Treg marker in humans?

A

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

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16
Q

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

A
  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
17
Q

What are the targets of CD4+CD25+ Tregs?

A
  • 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
18
Q

What are natural Tregs?

A

Generated in the thymus

19
Q

What are pTregs and iTregs?

A

Peripherally generated

20
Q

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

A

TH3 cell- induced by TGFbeta, produce TGFbeta

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

21
Q

What does IL10 do?

A
  • Inhibits T cell proliferation

* Inhibits APC function (less MHC2)

22
Q

What does TGFbeta do?

A 
• Inhibits T cell proliferation and effector function
• Inhibits B cell proliferation
• IgA isotype switch
• Inhibits macrophages
* But also has proliferative effects
23
Q

What are therapies targeting Tregs?

A
  • Induction of tolerance in transplantation or autoimmunity

* Reducing immunoregulation in cancer

24
Q

How can Treg function be decreased?

A
  • Removal of nTregs
  • Blockage of nTreg effector molecules (IL10, TGFbeta, CTLA-4)
  • Enhancement of effector T cells function
25
Q

How can Treg function be increased?

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

Immunology (17 decks)

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