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IMED2001 > Effector Mechanisms of T cell-mediated immunity > Flashcards

Effector Mechanisms of T cell-mediated immunity Flashcards

1
Q

What are the 2 stages of T cell recognition of protein antigens?

A

CMI begins with naive T cell activation and proliferation + differentiation into effector cells.

Differentiated effector cells and take out the infection by going to sites of infection and recognizing antigen anywhere in the body. (Together with macrophages and other leukocytes)

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2
Q

What are the 3 important CD4+ subsets in CMI?

A

TH1, TH2, and TH17

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3
Q

How do CD4+ cells regulate which subset of TH is produced?

A

Subsets are specific to types of microbes being fought so subset selection is based on microbe type.

Signal for differentiation is the cytokines produced by the APCs and other cells at time of antigen stimulation. (cytokines secreted by APCs vary depending on type of microbes)

Each effector T cell subset produces cytokines that amplify itself and inhibit other subsets.

Differentiation is associated with transcription factors and epigenetic changes in cytokine gene loci in commitment to a cytokine profile. signal transducers (STATs)

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4
Q

How do CD4+ cells regulate which subset of TH is produced?

A

Subsets are specific to types of microbes being fought so subset selection is based on microbe type.

Signal for differentiation is the cytokines produced by the APCs and other cells at time of antigen stimulation. (cytokines secreted by APCs vary depending on type of microbes)

Each effector T cell subset produces cytokines that amplify itself and inhibit other subsets.

Differentiation is associated with transcription factors and epigenetic changes in cytokine gene loci in commitment to a cytokine profile. signal transducers (STATs)

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5
Q

What drives production of TH1 cells?

A

Bacterial and viral intracellular infections

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6
Q

What cytokines drive TH1 differentiation?

A

IL-12 and IFN-γ (intracellular infections almost always use IFN-γ)

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7
Q

Which cells produce IL-12?

A

DCs and macrophages

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8
Q

What microbes drive production of TH1 cells?

A

Bacterial and viral intracellular infections

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9
Q

What cytokines drive TH1 differentiation?

A

IL-12 and IFN-γ

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10
Q

What cytokine do TH1 cells produce that further encourages differentiation into TH1 cells?

A

IFN-γ which promotes more TH1 development and inhibits TH2 and TH17 production.

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11
Q

Which cells produce IFN-γ?

A

NK cells (and already differentiated TH1 cells)

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12
Q

What microbes trigger activation of TH2?

A

Helminths

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13
Q

What cytokines are produced to activate TH2?

A

IL-4

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14
Q

What secondary messengers are produced by activation of TH2 cells?

A

STAT6

GATA-3

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15
Q

What secondary messengers are produced by activation of TH2 cells?

A

STAT6

GATA-3

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16
Q

What cells produce IL-4?

A

TH2 is the main source (positive feedback loop like IFN-γ in TH1)

Mast cells

Eosinophils

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17
Q

What infection triggers TH17 differentiation?

A

Extracellular bacteria and fungi

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18
Q

What cytokines are produced to activate TH17?

A

TGF-β, IL-6, and IL-23

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19
Q

What cytokines are produced to activate TH17?

A

TGF-β (mostly seen in mice humans less known), IL-6, and IL-23

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20
Q

What cytokines are produced in response to fungal infections and some bacteria?

A

IL-6

IL-1

IL-23

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21
Q

How do CTLs?

A

They produce enzymes that access the cell membrane and allow entry of enzymes into the cell inducing apoptosis.

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22
Q

How do CTLs?

A

They produce enzymes that access the cell membrane and allow entry of enzymes into the cell inducing apoptosis.

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23
Q

What 2 major pathways activate from T cell - mediated immune reactions?

A

Phagocyte with ingested microbes in vesicles activating inflammation and macrophages to induce the killing of microbes.

Direct killing of infected cells via cytotoxic action

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24
Q

`What proteins do naive T cells express to move to the high endothelial venule (HEV) in lymph node?

A

L-selectin which binds to L-selectin ligand on endothelial cells to facilitate adhesion of naive T cells to HEV.

LFA-1 which binds to ICAM-1 stopping T cell from moving around in HEV

CCR7 which binds to CCL19 or CCL21 which activates integrins and is importatn for chemotaxis (localizing action).

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25
Q

What proteins do activated T cells express?

A

E and P selectin ligand which binds E or P selectin on endothelial cells.

LFA-1/VLA-4 which binds to ICAM (more stable arrest on cytokine-activated endothelium)

CXCR3 which binds to CXCL10 (activation of integrins and chemotaxis)

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26
Q

What is the purpose of E and P selectin ligands on effector T cells?

A

Instigates adhesion of memory T cells to cytokine-activated endothelium at peripheral site of infection.

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27
Q

How is the function of effector T cells separated from that of naive T cells?

A

Effector T cells do not express CCR7 or L-selectin and are not drawn into lymph nodes as a result

28
Q

What molecule do naive T cells have that allow them to enter lymph nodes through HEVs?

A

CCR7 receptor and L-selectin.

29
Q

What do CCR7 receptors do in naive T cells?

A

Induces expression of LFA-1 on naive T cells to bind and enter HEV.

30
Q

What do T cells produce that are important for entry into lymph nodes?

A

Sphingosine 1-phosphate (S1P). Levels of S1P are higher in blood and lymph than in lymph nodes.

31
Q

What happens when S1P binds a S1P receptor? What does this mean?

A

It reduces expression of receptor S1PR1 which means when naive T cell enters the lymph node it starts to express more S1PR1 which triggers its entry into lymph node.

32
Q

What signals and adhesion molecules are important for effector T cells to function?

A

Activated T cells express high levels of ligands for E- and P- selectins and integrins LFA-1 and VLA-4.

33
Q

What promotes endothelial cells at site of infection to expose ICAM-1 and VCAM-1?

A

Cytokines such as TNF and IL-1

34
Q

Why don’t naive T cells end up in sites of infection and injury?

A

Because they don’t express ligands for E or P selectins nor for chemokines

35
Q

Is antigen recognition responsible for movement of effector T cells to sites of infection?

A

No, migration to infection sites is purely cytokine and chemokine mediated.

However, antigen recognition mediates which effector cells are retained at site of infection.

36
Q

Note about classifying CD4+ T cells:

A

They are not readily classified into TH1,2 and 17. There is some change between these types of cells and they can be converted into each other under some conditions.

37
Q

What cytokines do TH1 cells produce and what happens as a result?

A

IFNγ which results in macrophage activation and IgG production in response to intracellular microbes.

38
Q

Which CD4+ cell is involved in autoimmune diseases?

A

TH1

39
Q

What cytokines do TH2 cells produce?

A

IL-4

IL-5

IL-13

40
Q

What do TH2 cells activate?

A

Mast cells, eosinophils, IgE production, and alternative macrophage activation (helminth response)

41
Q

What diseases do TH2 cells cause?

A

Allergic reactions

42
Q

What cytokines do TH17 cells produce?

A

IL-17A

IL-17F

IL-22

43
Q

What kind of reactions do TH17 cells produce?

A

Neutrophilic, monocytic inflammation

44
Q

What pathogens do TH17 cells respond to?

A

Extracellular bacteria and fungi.

45
Q

What diseases are TH17 associated with?

A

Autoimmune and inflammatory diseases.

46
Q

What are the pathways that can result from IFN-γ production by TH1 cells?

A

Classical macrophage activation (enhanced microbe killing)

Complement binding and opsonizing IgG antibodies (stimulates antibody production)

IFN-γ also stimulates expression of MHCII and B7-1/B7-2 on macrophages and DCs to amplify T cell responses

47
Q

What receptor does macrophage use for phagocytosis of IgG opsonized pathogens?

A

Fc receptor

48
Q

Where are CD40 and CD40L receptors expressed?

A

On antigen-stimulated T cells the CD40L (ligand) is present and on the macrophages and B lymphocytes the CD40 is expressed

49
Q

What does the CD40 - CD40L interaction result in?

A

Promotes T cell activation by making APCs better at stimulating T cells.

Activation of macrophages in CMI

B cells produce high affinity isotype switched antibodies in humoral responses

50
Q

How does CD40-CD40L promote macrophage killing?

A

It allows production of reactive oxygen species, NO, and increases lysosomal enzymes which promote killing of microbes in phagolysosomes.

51
Q

What effects does CD40-CD40L interaction have on macrophages?

A

Promotes killing within phagolysosomes

Sectretion of cytokines (TNF, IL-1, and IL-12) which promote leukocyte recruitment as well as TH1 differentiation

Increased expression of MHC and costimulators on macrophage surface

52
Q

How do naive CD4+ T cells get activated by innate immune system?

A

APCs encounter microbes and produce IL-12 which stimulates naive CD4+ T cells to differentiate into TH1 cells and start producing IFN-γ.

Effector T cells activate more macrophages via IFN-γ and so more IL-12 is produced by the macrophages creating a positive feedback loop

(This is an example of cross talk between innate and adaptive immune system)

53
Q

What do TH2 cells do in response to encountering a pathogen?

A

They produce multiple cytokines which are important for helminth defence.

They activate B cells and mast cells to produce IgE antibodies

54
Q

What cytokines do CD4+ TH2 cells produce and what do these cytokines do?

A

They produce IL-4 which stimulates IgE and IgG production by B cells which result in mast cell degranulation and cytotoxic compound release.

They can produce IL-4 and IL-13 which together promote mucosal organ mucous secretion which inhibits entry of more helminth pathogens.

They produce IL-4 and IL-13 which activate alternative macrophages to enhance synthesis of extracellular matrix proteins for tissue repair.

They can produce IL-4, 10, and 13 which inhibit microbicidal activities of classical macrophages and suppress TH1 response.

55
Q

What cytokine triggers eosinophil activation?

A

IL-5,

56
Q

What do IgE antibodies do?

A

They coat helminths and then killer granules are produced by cells that bind to bound IgE

57
Q

What influences the type of CMI that is triggered?

A

The balance between Th1 and 2

58
Q

What do the cytokines produced by TH17 cells do?

A

IL-17 is the cytokine important for triggering responses that amplify inflammation and get leukocytes (monocytes+neutrophils) to site of infection

Stimulate antimicrobial defensin production

IL-17 and IL-22 maintain functional integrity of epithelial barriers in intestinal tract and other tissues

59
Q

What is the result of T cell inflammation triggering?

A

A stronger and more prolonged response to fungal and bacterial infections.

Stimulate production of defensins which are anti-microbial and function like endogenous antibiotics

60
Q

How do CD8 cells carry out their effector functions?

A

They recognize MHCI on infected cells and kill cells eliminating the ability for pathogen to spread.

61
Q

What are the recognition molecules involved in CD8 function?

A

MHCI and CD8 co-receptor

Surrounding these molecules are other signalling proteins as well as LFA-1 integrin (binding to ICAM creates an immune synapse)

62
Q

What cytotoxic compounds are released when cytotoxic T cells bind to infected cell?

A

Granzyme B (induces apoptosis) and perforin (perforates cell membrane)

Membrane protein FasL is also expressed which binds to death-inducing receptor Fas (CD95) on target cell.

63
Q

How does granzyme B carry out its function?

A

Cleaves and activates caspases present in the cytosol of target cells and whose major function is to induce apoptosis.

64
Q

How does perforin carry out its function?

A

Disrupts integrity of cell membrane and endosomal membranes which allows granzyme B to enter the cell and initiate apoptosis

65
Q

How does FasL (CD95) activate apoptosis?

A

It activates caspases and induces target cell apoptosis.

It does this without exocytosis of granules and has a minor role in killing by CD8

66
Q

How do CD4 and CD8 T cells cooperate in readicating intracellular infections?

A

CD4 T cells induce macrophages to destroy phagocytosed microbes by secreting IFN-γ and activating microbicidal mechanisms of macrophages.

If macrophages cant kill the pathogen and it escapes into cytoplasm they are killed by CD8 CTLs

IMED2001 (44 decks)

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