L9-T Cell Effector Responses Flashcards

(58 cards)

1
Q

What is the role of T cells?

A

Plays a major role in cell mediated immunity in that it is important in eliminating and providing defense against intracellular microbes e.g. bacteria and viruses.

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2
Q

What is the main role for CD4+ T cells?

A

CD4+ T cells “help” activate macrophage to induce the production of ROS, NO, lysosomal enzymes to kill ingested microbes.

They also help to induce inflammation responses of other leukocytes to kill extracellular microbes e.g. fungi and helminths.

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3
Q

What is the main role for CD8+ T cells?

A

CD8+ T cells can recognise and kill the infected cells, thus eliminating the reservoir of infection.

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4
Q

How can you tell T cells apart?

A
  1. Categorised based on maturation state

2. Categorised based on function

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5
Q

Describe the maturation state of T cells.

A

Naive T cells (CD4+ or CD8+)

Meets antigen:

  1. Effector T cell or
  2. Memory T Cell

Memory cell:

  1. Effector memory T cell or
  2. Central Memory T cell
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6
Q

What are central memory T cells?

A

Central memory T cells (TCM cells) express CD45RO, C-C chemokine receptor type 7 (CCR7), and L-selectin (CD62L). … These memory T cells lack lymph node-homing receptors and are thus found in the peripheral circulation and tissues.

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7
Q

How are memory T cells different from naive T cells?

A

Memory T cells are a subset of infection- and cancer-fighting T cells (also known as a T lymphocyte) that have previously encountered and responded to their cognate antigen; thus, the term antigen-experienced T cell is often applied. In comparison to naive T cells, which are T cells that have not been exposed to antigens yet, memory T cells can reproduce to mount a faster and stronger immune response.

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8
Q

What happens to memory T cells once the infection has been cleared?

A

These cells would reverse from the active effector role to a state more similar to naive T cells and would be “turned on” again upon the next antigen exposure.

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9
Q

Why don’t memory T cells die after infection has been cleared, like effector T cells?

A

Memory T cells are instead produced by naive T cells that are activated, but never entered with full-strength into the effector stage.

The progeny of memory T cells are not fully activated because they are not as specific to the antigen as the expanding effector T cells.

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10
Q

Where can you find naïve T cells that have not yet encountered antigen?

A

Naïve T cells have not encountered an antigen and preferentially circulate through the secondary lymphoid organs (e.g. lymph nodes) via the lymphatics system.

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11
Q

Where does initial activation of naïve T cells occur?

A

Initial activation of naïve T cells usually occurs in secondary lymphoid organs (e.g. lymph nodes)

  • When naïve T cells recognise their cognate antigens presented by antigen presenting cells
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12
Q

Why do memory T cells live longer than effector T cells?

A

Studies on T cell turnover indicate that most peripheral T cells can remain in a resting state for long periods (months in rodents and years in humans). Due to;

  • Increased levels of anti-apoptotic proteins (e.g. Bcl-2)
  • Undergo slow proliferation and able to self-renew
  • Maintenance is dependent on cytokines only (e.g. IL-7)
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13
Q

What happens when naïve T cells are presented with antigen by a APC?

A

Naïve T cell that recognize the antigen undergo clonal expansion and differentiate into effector or memory T cells

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14
Q

What happens once effector T cells are activated?

A
  • Enter blood circulation and preferentially migrate to peripheral tissue sites of infection
  • Cells that recognize antigens in the tissues are retained and further activated to elicit their function.

NOTE: Migration of cells are mediated by chemokine and adhesion molecules.

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15
Q

After antigen recognition, 3 major processes must occur. What are they?

A

1) Produce cytokines and cytokine receptors (e.g. IL-2)
2) Proliferate and undergo clonal (TCR with same specificity) expansion
3) Differentiation into effector “short-lived” or memory “long-lived” cells

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16
Q

List some characteristics of memory T cells

A

1) Enhanced and more rapid responses to antigens than naïve T cell
2) Generate “new” effector T cells when re-encounter with the same antigen- e.g. Vaccination with inactivated or live attenuated virus or peptides
3) “Long-lived” T cells (compared to effector T cell)
4) Have different receptor expression patterns to naïve T cells.

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17
Q

What receptor patterns do naïve T cells have?

A

CD45RA+
CD25lo
CD127hi

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18
Q

What receptor patterns do effector T cells have?

A

CD45RO+
CD25hi
CD127lo

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19
Q

What receptor patterns do memory T cells have?

A

CD45RO+
CD25lo
CD127hi

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20
Q

What signals are required for T cell activation?

A

1) Antigens presentation (MHC ➡️ TCR)

  • CD8 ➡️ MHC class I
  • CD4 ➡️ MHC class II

2) Co-stimulatory molecules

  • CD28 ➡️ B7 (CD80/86) = activation
  • CTLA-4 ➡️ CD80/86 = inhibition

2) Cytokines

  • Proliferation (IL-2)
  • Differentiation (IFNγ + IL-12 ➡️ Th1)
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21
Q

What signal causes T cell inhibition?

A

CTLA-4 ligating with B7. It has higher affinity biding compared to CD28 to CD28 cannot bind.

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22
Q

Antigen presented by MHC class I on antigen-presenting cells is recognized by TCR on which type of T cells?

A

CD8+

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23
Q

Antigen presented by MHC class II on antigen-presenting cells is recognized by TCR on which type of T cells?

A

CD4+

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24
Q

Name an adhesion molecule on T cells

A

Leukocyte function-associated antigen-1; LFA-1

25
What does LFA-1 do?
Adhesion molecule on T cells that recognise their ligand on APC (e.g. intercellular adhesion molecule-1; ICAM-1) and stabilise the binding of the T cells to the APC
26
Describe the affinity of LFA-1 on naïve T cells then how it changes upon antigen recognition.
LFA-1 on naïve T cell is initially at a low affinity state. Antigen recognition increases the affinity of that cell’s LFA-1.
27
Name the antigen recognition receptor and ligand involved in T cell activation.
TCR: MHC
28
What is the second signal for T cell activation?
T cell co-stimulators molecules B7:CD28 (B7.1=CD80 or B7.2=CD86) =activation CTLA-4 =CD80/86 = inhibition CD40:CD40L ICOS:ICOSL Remember signal 1: Antigen presentation (MHC:TCR) Signal 3: cytokines
29
“Resting” APC have no or low B7 expression. Why is this the case?
* T cell anergy - “unresponsiveness” | * Maintain tolerance to self antigens
30
How is B7 expression increased on APC?
* Expression of B7 increase after activation of APC * Microbes binding to innate receptors (e.g. TLR) * Activated by cytokines (e.g. IFNγ)
31
What is the relationship between CD40:CD40L?
CD40 is a costimulatory protein found on antigen-presenting cells and is required for their activation. The binding of CD40L on TH cells to CD40 activates antigen presenting cells and induces a variety of downstream effects. E.g. - Increase expression of B7 molecules - Induce cytokine production (e.g. IL-12) to promote T cell differentiation
32
Describe macrophage activation.
In the macrophage, the primary signal for activation is IFN-γ from Th1 type CD4 T cells. The secondary signal is CD40L on the T cell which binds CD40 on the macrophage cell surface. As a result, the macrophage expresses more CD40 and TNF receptors on its surface which helps increase the level of activation. The increase in activation results in the induction of potent microbicidal substances in the macrophage, including reactive oxygen species and nitric oxide, leading to the destruction of ingested microbe.
33
What is the function of ICOS:ICOSL?
Stands for (inducible costimulator) Follicular helper T-cell-dependent antibody response Related to CD28, ICOS promotes T-cell/B-cell collaboration through the CD40 (B-Cell-Associated Molecule CD40)/CD40L (CD40 Antigen Ligand) pathway. The outcome of such interaction is required for both lymphocyte activation and development of adaptive immunity and has a key role in promoting Ig (immunoglobulin) isotype switching.
34
What is the function of CD28 for mediated activation of T cells?
1. Promote T-cell survival= ↑ anti-apoptotic proteins (e.g. Bcl-2) 2. Enhanced proliferation= ↑ IL-2 and IL-2R, ↑ cyclins, ↓ cell cycle inhibitors 3. Differentiation into effector and memory cells= multiple mechanisms
35
What are some inhibitor co-receptors?
Cytotoxic T-Lymphocyte Antigen-4 (CTLA-4) Programmed death receptor-1 (PD-1)
36
What does CTLA-4 stand for?
Cytotoxic T-Lymphocyte Antigen-4
37
What is the function of Cytotoxic T-Lymphocyte Antigen-4 (CTLA-4)?
- Inhibitory receptor of the CD28 family - It has a higher affinity for B7 molecules than CD28 - It competitively inhibit binding of CD28 to B7
38
What does PD-1 stand for?
Programmed death receptor-1
39
What is the function of PD-1?
- Inhibitory receptor of the CD28 family | - Binds PD-L1 or PD-L2 on APC and inhibit T-cell response
40
How often is CD28 receptor expressed and when does CTLA-4/PD-1 start to regulate T-cell response?
- CD28 receptors are constitutively expressed on T cell | - CTLA-4/PD-1 are only expressed after T-cell activation (1-2 days)
41
Why is it so important to have inhibitor co-receptors?
- Inflammation = No/low expression of inhibitory receptors - Impaired immune response = High expression of inhibitory receptors
42
Why does Rheumatoid arthritis (inflammation) occur?
Too much immune activation, not enough inhibitory signal
43
How do you treat Rheumatoid arthritis?
Treat with CTLA-Ig (mimics CTLA-4 receptor), blocking B7 interaction with CD28 and inhibit T-cell activation
44
Explain how therapeutic immune modulator can be used for cancer (impaired anti-tumour response)
- Too much immune inhibition - Treat with anti-CTLA (blocking antibody), blocking B7 interaction with CTLA-4, allows CD80/86 to interact with CD28 and promote T-cell activation
45
What is the third signal of T cells?
Cytokines
46
What is IL-2?
It is an autocrine growth factor which amplify T cell response
47
How does IL-2 amplify T cell response?
- Induces expression of IL-2 receptors on T cells - T cell that recognize antigens produce IL-2 and respond to it - Stimulate the survival, proliferation (clonal expansion) and differentiation of antigen-activated T-cells (Naïve = effector & memory)
48
Naïve CD4+ T cell differentiate into distinct subsets to activate different groups of effector cells specialized in combating different types of pathogens. What is differentiation dependent on?
• Differentiation is dependent on the signature cytokines produced by: 1) APC that encounter different microbes developing into different subsets of APC and secreting distinct sets of cytokines 2) The T-cells themselves and other nearby cells (e.g. NK cells-IFNγ) • Dysregulation of each type of response may lead to different diseases
49
TH1 cells activated have which signature cytokines to what are the immune regulators they target and what is the host defence?
IFNy IL-12 Macrophage activation IgG production Defence: intracellular microbes
50
TH2 cells activated have which signature cytokines to what are the immune regulators they target and what is the host defence?
IL-4 IL-5 IL-13 Mast cell, eosinophil activation, IgE production; “alternative” macrophage Defence target: helminthic parasites
51
TH17 cells activated have which signature cytokines to what are the immune regulators they target and what is the host defence?
IL-17A IL-17F IL-22 Neutrophil is monocyclic inflammation ‘Defence target: extracellular bacteria/fungi
52
Explain the polarisation of Th subsets
T-cell subsets are defined by cytokine pattern. T cells of multiple lineages and at multiple stages in their differentiation can be driven to become polarized into different T-cell subsets if they have not been previously committed.
53
What are the stages involved with polarisation of Th subsets?
STAGE 1 – Induction by the 3 signals TCR:MHC, costimulators & cytokines = Cytokines induces transcription factors STAGE 2 – Commitment = Epigenetic changes cause genes that encode the subsets’ cytokine to be more accessible and vice versa (inaccessible) STAGE 3 – Amplification (polarization) = Cytokines produced promote the development of this subset and inhibits other Th subsets (e.g. Th1 inhibits Th2)
54
What is alternative macrophage activation by Th2 cells?
M2 macrophage may be antiinflammatory and are also important in tissue repair and fibrosis. IL-10, TGFb = anti-inflammatory effect Proline polyamines, TGFb = wound repair, fibrosis
55
What is the difference between macrophage activation and how it differs from the alternative pathway.
M1 macrophage are microbicidal, they may create harmful inflammation. M2 macrophage may be antiinflammatory and are also important in tissue repair and fibrosis.
56
What is the direct and indirect way CD4+ T cell help naïve CD8+ T cell differentiate to effector or memory CD8+ T cells?
Direct: CD4+ helper T cells produce cytokines that stimulate CTL differentiation Indirect: CD4+ helper T cells enhance the ability of APCs to stimulate CTL differentiation
57
What is the function of zCD8+ T cells?
Killing other cells (e.g. infected cells) Secrete cytokines (e.g. IFNγ)
58
What is the function of regulatory T cells (Treg)
• Suppress and prevent immune response - e.g. To self antigens (prevent autoimmune disease) • Maintain self tolerance