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HDM Exam 1 and 2 > T-Cell Mediated Immunity > Flashcards

T-Cell Mediated Immunity Flashcards

1
Q

What are the 2 signals of Lymphocyte Activation?

A
  1. Antigen binding to antigen receptor (MHC –> TCR)

2. Molecule induced by innate response (costimulator, complement fragment) binding to its receptor

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2
Q

When the 2 signals are provided, what happens?

A

Lymphocyte proliferation and differentiation

Adaptive Immune Response

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3
Q

Name the effector function of T-Helpers.

A

Activation of macrophages, B-cells, and other cells

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4
Q

Name the effector function of cytotoxic-T cells.

A

Killing of infected “target cells”, macrophage activation

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5
Q

Describe the overall mechanism of T-helpers.

A

When an APC travels to a lymph node, Th binds to MHC Class 2 and upregulates CD40L expression.
CD40L binds to CD40 on APC leading to greater expression of MHC and greater activation of Th (Co-stimulation).

After activation, cells dissociate and Th-cell proliferates. Matures into Effector, Memory, and Regulator cells.

Effector Th stimulates B-cells (Th1), Macrophages (Th2), and Cyt-T (Th2)

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6
Q

Describe the overall mechanism of Cyt-Ts.

A

When an APC travels to a lymph node, Cyt-T binds to MHC Class 1 and upregulates CD40L expression. CD40L binds to CD40 on APC leading to greater expression of MHC and greater activation of Cyt-T (Co-stimulation).

After activation, cells dissociate and Cyt-T proliferates. Travels to area of infection. Identifies infected cell, which displays Ag on MHC Class 1 and is activated. Cyt-T destroys infected cell through apoptosis. Phagocyte digests remains.

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7
Q

What is found on the surface of a Naive T-cell?

A 
CD4 or CD8, CD28
HLA/MHC Class 1
TCR complex + CD3
LFA-1 and VLA-4 Adhesion molecules 
Chemokine receptors
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8
Q

Naive T-cells are activated by what cell?

A

Dendritic Cells (DC)

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9
Q

Memory T-cells are activated by what cell?

A

B-cells and Macrophages

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10
Q

How do T-cells enter the lymphoid tissue? Be Specific.

A

They enter through the HEV in the cortex. They weakly adhere to HEV by selecting. T-cells have L-selectin, which binds to L-selectin ligand on HEV.

The CCR7 on the T-cell will then bind to CCL19/21, which turns the integrin receptor from a low-affinity to high-affinity state.

The integrin (LFA-1) on T-cell binds to ICAM-1 on HEV.

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11
Q

How do T-cells leave the lymphoid tissue? What happens when it enter the peripheral venule? Be Specific.

A

They leave through Efferent lymphatic vessels. They leave with S1P (modulation of CCR) on S1PR1.

Once they reach the peripheral tissue, E/P-Selectin will bind to its ligand on venule. CXCR3 will then bind to CXCL10 or others. Changes affinity state of integrin.

Integrin (LFA-1 or VLA-4) binds to ICAM1 or VCAM-1.

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12
Q

Name the accessory molecules responsible for antigen recognition, signal transduction, and adhesion on T-cells.

A

Antigen Recognition: TCR –> CLASS 2 MHC

Signal Transduction:
CD3 (with ITAM domains)
CD4 –> CLASS 2 MHC (B2)
CD28 –> B7/CD80 (antigen presenting cells)

Adhesion:
LFA-1 –> ICAM-1

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13
Q

What accessory molecules on T-cells inhibit Signal transduction?

A

CTLA-4 –> B7/CD80
PD-1 with ITIM –> PDL-1/2

CTLA4 is constitutively expressed on T-regs (competitively interacts with CD80), but sequestered on mature, naive T-cells.

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14
Q

When an Antigen is presented to a T-cell, how does integrin activity change? Explain.

A

In normal conditions, without Ag, the integrin is in a low-affinity state so there is weak adhesion and no t-cell response.
When Ag is presented, Ag-recognition as well as chemokines release changes integrin affinity state from Low to High. This results in clustering of integrins leading to strong T-cell-APC adhesion and T-cell response.

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15
Q

What happens during T-cell activation? (Exclude adhesion)

A

Antigen recognition happens by interaction between MHC Class 2 and TCR + CD4
CD40L expression is upregulated on T-cell and binds to CD40 (constitutively expressed on APC), leading to APC activation.
B7/CD80 expression is upregulated on APC and binds to CD28 (constitutively expressed on T-cell). APC also releases cytokines (IL-12). Combined, these enhance T-cell activation and proliferation.

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16
Q

Explain in more detail T-cell activation inside T-cell.

A

The immunological synapse forms.

2 tryosine kinases are activated:
FYN and LYK (found on CD4/8) = phosphorylate ITAMs, which recruit Zap-70 on zeta chain. Activation of Zap-70 leads to activation of PLCy1. It also leads to the activation of PI3-Kinase and GDP/GTP exchange factor from adaptor proteins.

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17
Q

What happens with the activation of PLCy1?

A

Cytosolic Ca2+ increased –> increase in calcineurin –> NFAT (transcription factor - nuclear factor activated T-cells)

Diacylglycerol (DAG) increased –> PKC –> NF-kB and AP-1 (transcription factor)

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18
Q

What happens with activation of GTP/GDP exchange factor?

A

GTP/GDP exchange on RAS and RAC –> ERK, JNK –> NF-kB, AP-1

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19
Q

What happens with activation fo PI3-Kinase?

A

Activation of PI3-Kinase –> PIP3 –> Akt, mTOR –> increased protein synthesis and NF-kB, AP-1

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20
Q

What cytokine does NFAT up regulate?

A

IL-2

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21
Q

Activation of T-cells triggers a cascade of protein production. Can you name them and when they start to appear?

A

Transcription factors c-FOS and c-Jun start being expressed in minuets. c-Myc in hours.

CD40 ligand and FAS ligand are expressed in hours

IL2 is expressed in hours along with IL2Ra (CD25); IFN-y and IL-4 can takes days

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22
Q

What happens when T-cells bind to Ag without binding to co-stimulatory ligands or cytokine support?

A

It will not become activated. It becomes TOLERANT (unresponsive or anergic).
Maybe one reason why self-ags are not attacked.

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23
Q

What are the cytokines produced by T-cells?

A

IL-2, IL-4, IL-5, IL-17, IL-22, also IL-10
IFN-y
TGF-B

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24
Q

What is the action of IL-2?

A

Secreted by ACTIVATED T-cells

Responsible for T-cell proliferation and regulatory t-cell survival

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25
Q

What is the action of IL-4?

A

Secreted by CD4-Ts and Mast cells

Responsible for B-cell switching to IgE

26
Q

What is the action of IL-5?

A

Secreted by CD4-Ts, Mast cells, Innate Lymphoid cells

Responsible for the activation of eosinophils

27
Q

What is the action of IL-17?

A

Secreted by CD4-Ts and other cells
Responsible for the stimulation of acute inflammation
Also has some IL-22 function

28
Q

What is the action of IL-22?

A

Secreted by CD4-Ts, NK cells, Innate Lymphoid cells

Responsible for the maintenance of epithelial barrier function

29
Q

What is the actin of IFN-y?

A

Secreted by CD4-Ts, CD8-Ts, NK cells
Responsible for activation of classical macrophages against intracellular microbes.
Activated B-cells to stimulate complement binding and class switching
Stimulates Class 2 MHC and CD80 expression.

30
Q

What is the action of TGF-B?

A

Secreted by CD4-Ts and other cells

Responsible for the inhibition of T-cell activation; differentiation of regulatory T cells

31
Q

What is the action of IL-10?

A

Secreted by T-regs and alternative macrophages

Same action as TGF-B, inhibition fo T-cell activation

32
Q

How does Il-2 promote proliferation?

A

It is an autocrine signal. IL-2 secreted by an activated T-cell will bind to IL-2Ra (CD25) on the same cell. IL-2R is constitutively expressed as low affinity receptor. Binding promotes proliferation and differentiation.

33
Q

Explain Cross-Presentation.

A

APCs (DCs) can present CD4s AND CD8s. IL-2 released by activated helper-Ts can help skip multiple steps in Cyt-T activation leading to water expansion & differentiation.

34
Q

Explain Trapping.

A

Naive T-cells have been presented an Ag within 2 days. During this time, CD69 expression is increased. It binds to S1PR1 and prevents migration of T-cells out of efferent lymphatic vessels. This gives them enough time to proliferate and differentiate. After 5 days, the effector cell can emigrate out.

**Cyt-T cells will emigrate immediately, but T-helpers will stay to activate B-cells.

35
Q

Describe Th1.

A

Proliferate in response to IL-12 (DC/macrophages) and IFN-y (NK-cells)

Release cytokines that activate Macrophages (IFN-y), also DCs and NKs. Also secretes IL-2.

Host defense: Intracellular pathogens

Role in disease: Autoimmunity, chronic inflammation

36
Q

What happens intracellularly in a Naive T-cell after interaction with IFN-y and IL-12?

A

IL-12 activates transcription factor STAT4. IFN-y activates STAT1, which turns into T-bet. Both involved in production of IFN-y, which can self-amplify cell and differentiate into Th1 cells, which secrete IFN-y and IL-2. (Also TNF-a)

37
Q

Describe Th2.

A

Proliferates in response to IL-4 (Mast cell).

Secretes IL-4, IL-5, IL-13 to activate Eosinophils. Also to activate mast cells and alternative macrophages.

Isotype class switching to IgE in B-cells

Occurs in response to allergens and helminths
Also–> Mucus production, Peristalsis, IgA production

38
Q

What happens intracellularly in a Naive T-cell after interaction with IL-4?

A

IL-4 binding activates STAT6. STAT6 and GATA3 act as transcription factors to produce IL-4 and differentiate into Th2.

39
Q

Describe Th17.

A

Proliferates in response to IL-1, IL-6, (TGF-B?).

Secretes IL-17, IL-22 to recruit and activate Neutrophils.

Host defense: Extracellular bacteria and fungi

Role in disease: Autoimmunity; inflammation, leukocyte recruitment, important in barrier function and neutrophil activation

40
Q

What happens intracellularly in a Naive T-cell after interaction with IL-1/6 and TGF-B?

A

IL-6 activates STAT3, TGF-B activates RORyt.

41
Q

Describe Tfh.

A

Secretes IL-21 (and IFN-y or IL-4) to target B-cells for antibody production
Host defense: extracellular pathogens
Role in disease: Autoimmunity (autoantibodies)

42
Q

Describe the Migration of Activated Th cells.

A

Activation occurs in the medullary area with antigen presentation

CCR7 expression decreases, CXCR5 increases –> migration of activated T-cells to EDGE of follicular zone where B-cells are

Activated T-cells start expressing CTLA-4

43
Q

Cytokines vs. Class Switching. What happens?

A

When adding mitogen (LPS) to Naive B-cell, class switching does not happen.

But when you add IL-4 + LPS, you have class switching producing IgG1 and IgE

TGF-B + LPS –> IgG2b, IgA

44
Q

Describe T-Regulatory Cells.

A 
CD4, CD25
Influenced by IL-2 and TGF-B
Secrete IL-10 and TGF-B
Constitutively express CTLA-4 and CD25
CTLA-4 binds to CD80 and shuts down IL-2 production
However, CD80 binds more avidly to CD28
Transcription factor = FOXp3
45
Q

Describe Gamma Delta T cells.

A

Less than 5% of T-cells
Found in epithelial boundaries
Ag restricted - limited diversity of peptides recognized, but can recognize NON-PROTEIN Ag

46
Q

Why is a predominant Th2 response to intracellular microbes bad?

A

It can lead to poor disease outcomes. This is because Th2 cell inhibit microbial activity of macrophages and instead active alternative macrophages.

47
Q

In peripheral tissue, no every T-cell that enter the area is specific for that Ag. Why?

A

The selectins and chemokines are not antigen-specific. So you will have multiple T-cells enter the area. Those that are specific stay. Those that aren’t leave.

48
Q

How are Ag-specific T-cell retained in the peripheral tissue?

A

New selecting and integrins are expressed upon activation that help retain the T-cells.
VLA –> ICAM and Fibronectin
P & E Selectin ligands
CD44 –> hyaluronan

49
Q

What cytokines are required by memory T-cells for survival?

A

IL-7 and IL-15

50
Q

Describe the production of memory cells.

A

Naive T-cell will become effector T-cells (CD8 > CD4)
During homeostasis, many of the effector Ts undergo apoptosis, while some become memory T-cells.

Memory Ts express high levels of anti-apoptotic protein, BCL-2
Will require reactivation to regain effector function and can respond more rapidly than naive Ts.

51
Q

When does T-cell exhaustion occur?

A

During chronic infection, exhausted T-cells are unable to respond to virus. This is because of the increased expression of CTLA-4 and PD-1. T-cells cannot keep up with virus.

52
Q

What happens when you transfer “Immune” T-cell to a non-immune individual? What happens when you transfer immune serum?

A

When you transfer Immune T-cells, you can transfer immunity to intracellular bacteria to the non-immune individual.
However, immune serum does not protect against intracellular microbes. This is because serum has antibodies that cannot reach intracellular microbes.

53
Q

What is the major difference between effector T-cells and Naive T-cells?

A

Naive T-cell require co-stimulation via B7-CD28 interaction, while Effector T-cell can respond to Ag without co-stimulation.

54
Q

What are the two mechanisms of Cyt-T killing?

A

Granzymes carried by perforins –> activate caspases

FAS (CD95) on target cells binding to FASL on activated Cyt-T –> activates caspase –> apoptosis

55
Q

What is significant about IFNa/B?

A

Inhibits replication of viruses
Increases expression of MHC-1 on other infected cells
Enhances NK killing

56
Q

What is Antibody Dependent Cell-mediated Cytotoxicity?

A

NKs, macrophages/monocytes, neutrophil, eosinophil
Identify target though IgG antibody
Kill by lytic enzymes, perforin, TNF

57
Q

What is the evasion mechanism of mycobacteria?

A

Inhibition of phagolysosome fuse, survives in phagosome

58
Q

What is the evasion mechanism of HSV (Herpes)?

A

Inhibition of Ag-presentation - interferes with TAP at ER

59
Q

What is the evasion mechanism of Cytomegalovirus?

A

Inhibition of Ag-presentation - inhibition of proteosomal activity or removal of class 1 MHC from ER

60
Q

What is the evasion mechanism of Epstein-Barr Virus?

A

Inhibition of Ag-presentation - inhibition of proteosome

Production of IL-10 –> inhibits macrophage activation

61
Q

What is the evasion mechanism of Pox Virus?

A

Inhibition of Effector Cell activation –> production of soluble cytokine receptor that competes with and prevents cytokine activation of effector cell

HDM Exam 1 and 2 (7 decks)

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