March 12 - Negative Regulation and T regs

What does negative regulation involve?

Receptors, mechanisms and cell types like Tregs

What is the time frame for immune response contracting?

10-14 days

After the AG is removed what happens to most lymphocytes?

They undergo apoptosis

What do Treg cell help with for apoptosis?

May help to quell responses by releasing inhibitory cytokines

What is clonal contraction?

Most newly generated B and T cells are lost at the end of the primary immune response. After Ag is cleared most of the effector cells are no longer required. Cells die by apoptosis

What is the intrinsic pathway of cell death via apoptosis?

• IL2Ralpha and other cytokine receptors expression is transient

• Lack of signaling through these receptors → absence of surviving signal→ Apoptosis

How does the extrinsic pathway of apoptosis work?

• Triggered by Fas-FasL binding

• Involves CTLs

• Leads to apoptosis

What percentage of effector T cells die - leaving behind antigen-specific memory T cells?

At least 90%

What do memory cells do?

Respond with heightened reactivity to a subsequent exposure to the same antigen. Secondary response is faster and more robust/effective

What do CTLA-4s do?

Bind to B7 and have an inhibitory response for T cell activation

What does CTLA-4 induce?

• Downregulates T cell activation, proliferation and survival

• Binds to B7.1/B7.2 with higher affinity than CD28 and shuts down signaling pathways - preventing excessive and uncontrolled immune responses

How does CTLA-4 get activated? How long does that last?

They are intracellular → Phosphorylation allows it to be expressed on the cell membrane (a post-translational regulation)

Induced within 24 hours after activation, peaks 2-3 days post-stimulation

How many B7 molecules can CTLA-4 bind to?

Two

What does B7 binding show?

Sequesters B7 and prevents binding to CD28

What can happen in some cases, what can happen to B7 from CTLA-4?

CTLA-4 can strip B7 molecules from antigen-presenting cells and remove them from APC surfaces

What is expressed by naive T cells?

CD28

What is induced after the activation of naive T cells after receiving signals 1 and 2 to prevent too many clonal T cells?

CTLA-4 - Makes activated T cells less sensitive than naive T cells to stimulation by APCs and restricting IL-2 production and prevents overgrowth of lymphocytes

What is PD-1?

Inhibitory/regulatory receptors

What can PD-1 be expressed on?

Activated T cells

What does PD-1 bind to?

• PDL-1 (expressed by many cells)

• PDL-2 (on APCs during inflammation)

What does PD-1 signaling cause?

Down-regulates T cell activation/proliferation and function

What are markers of T cell “exhaustion”?

PD-1 which occurs in chronic diseases

What is signal 3 for iTregs?

• IL-2 and TGFbeta

What are the effector cytokines for iTregs?

IL-10 and TGFbeta (anti-inflammatory cytokines0

What is the master transcriptional regulator of iTregs?

FoxP3

What do iTregs do?

Suppress immune responses, specifically maintain immune tolerance to self-antigens (prevent autoimmunity)

What are the characteristics of natural Tregs?

• Thymus-derived

• Selected for high affinity for self peptides → but to dampen the immune response to them

• Express TCR, CD4, IL2Ralpha and CTLA-4

• They are unable to provide IL-2 so they rely on other cells

• Express FoxP3

What are the characteristics of induced Tregs (iTregs)?

• Arise in the periphery from CD4+ T cells

• Express TCR, CD4, IL2Ralpha and CTLA-4

• Express FoxP3 (some exceptions)

What do both induced and natural regulatory T cells secrete and do?

• Secrete IL-10 and TGFbeta

• Represses other immune cells, mainly T cells

What do Tregs deplete the local area of?

Stimulating cytokines

What do Tregs express for negative regulation?

Express IL2Ralpha (CD25) chain → sequester IL-2

What does B7 sequestration by CTLA-4 cause?

• Inhibit APC activity by reducing co-stimulatory molecule expression and pro-inflammatory cytokine secretion

• Reduce T cell differentiation and activation

Which immunosuppressive cytokines do Tregs produce?

IL-10 and TGFbeta

How do Treg cells kill T cells?

Through T cells through granzymes and metabolic disruption

What does IL-10 do?

Inhibit production of TH1 and TH17 cytokines

What does TGF-beta do?

Inhibits T cell proliferation and inhibit the development and function of TH1 and TH2

What are Tregs specific to?

Specific to peptides that are self or safe non-self

What do nTregs recognize?

• Recognizes self-peptide:MHC→ arises in thymus

What do iTregs recognize?

• Peptide:MHC (could be self or commensal Ag) → arises in periphery

What can cause allergies or autoimmunity?

T cells can escape and can cause allergies or autoimmunity if the majority of autoreactive T cells are deleted in the development process in the thymus

If a treg recognizes its p:MHC on an APC what happens?

→ APC presenting self-peptides

• T regs secrete cytokines that will inhibit neighbouring and potentially autoreactive T cells that recognize other self peptides:MHC being presented by the same cell from getting activated