March 12 - Negative Regulation and T regs

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41 Terms

1

What does negative regulation involve?

Receptors, mechanisms and cell types like Tregs

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2

What is the time frame for immune response contracting?

10-14 days

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3

After the AG is removed what happens to most lymphocytes?

They undergo apoptosis

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4

What do Treg cell help with for apoptosis?

May help to quell responses by releasing inhibitory cytokines

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5

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

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6

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

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7

How does the extrinsic pathway of apoptosis work?

  • Triggered by Fas-FasL binding

  • Involves CTLs

  • Leads to apoptosis

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8

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

At least 90%

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9

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

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10

What do CTLA-4s do?

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

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11

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

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12

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

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13

How many B7 molecules can CTLA-4 bind to?

Two

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14

What does B7 binding show?

Sequesters B7 and prevents binding to CD28

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15

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

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16

What is expressed by naive T cells?

CD28

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17

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

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18

What is PD-1?

Inhibitory/regulatory receptors

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19

What can PD-1 be expressed on?

Activated T cells

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20

What does PD-1 bind to?

  • PDL-1 (expressed by many cells)

  • PDL-2 (on APCs during inflammation)

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21

What does PD-1 signaling cause?

Down-regulates T cell activation/proliferation and function

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22

What are markers of T cell “exhaustion”?

PD-1 which occurs in chronic diseases

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23

What is signal 3 for iTregs?

  • IL-2 and TGFbeta

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24

What are the effector cytokines for iTregs?

IL-10 and TGFbeta (anti-inflammatory cytokines0

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25

What is the master transcriptional regulator of iTregs?

FoxP3

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26

What do iTregs do?

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

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27

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

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28

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)

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29

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

  • Secrete IL-10 and TGFbeta

  • Represses other immune cells, mainly T cells

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30

What do Tregs deplete the local area of?

Stimulating cytokines

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31

What do Tregs express for negative regulation?

Express IL2Ralpha (CD25) chain → sequester IL-2

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32

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

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33

Which immunosuppressive cytokines do Tregs produce?

IL-10 and TGFbeta

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34

How do Treg cells kill T cells?

Through T cells through granzymes and metabolic disruption

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35

What does IL-10 do?

Inhibit production of TH1 and TH17 cytokines

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36

What does TGF-beta do?

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

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37

What are Tregs specific to?

Specific to peptides that are self or safe non-self

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38

What do nTregs recognize?

  • Recognizes self-peptide:MHC→ arises in thymus

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39

What do iTregs recognize?

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

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40

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

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41

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

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