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STEP Physiology > I9 > Flashcards

I9 Flashcards

1
Q

What is an effector T cell?

A

a daughter cell of an activated T cell that has fully differentiated and is ready to perform its effector function.

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2
Q

How are effector T cells different from naïve T cells?

A

(1) They do not require co-stimulation to be activated to perform their effector function. The only signal they need is recognition of their cognate peptide presented by an MHC molecule.(2) They express an array of surface adhesion molecules that direct them to appropriate tissues and inflammatory sites.

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3
Q

L-selectin (or CD62L) is expressed on the surface of what kinds of T cells?

A

naïve CD4+ and CD8+ T cells. and CD4 effector cells

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4
Q

What does L-selectin (CD62L) do?

A

It binds to adhesion molecules (Glycam-1 and CD34) that are found on the surface of endothelial cells that line the high epithelial venules on secondary lymphoid tissues. Only cells that express L-selectin can enter these tissues.

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5
Q

Why is L-selectin not found on effector CD8 T cells?

A

because effector CD8 T cells have no positive role in a secondary lymphoid tissues, while they would have a destructive function. They would kill any APC that presents their cognate peptide on MHC molecules.

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6
Q

Why do CD4 effector cells do need to have L-selectin on their surface?

A

so that they can cycle through the various secondary lymphoid tissues to serve as the secondary activators of antigen-specific B cells.

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7
Q

Which T cells express VLA-4 on their surface?

A

upregulated on effector T cells

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8
Q

What does VLA-4 do?

A

This integrin receptor binds to an integrin ligand called VCAM-1 that is expressed on activated endothelial cells. When VLA-4 binds to VCAM-1, it facilitates the movement of the effector cell across the vascular endothelium into an inflammatory site.

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9
Q

What kinds of T cells is LFA-1 present on the surface of?

A

All T cells

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10
Q

What kinds of T cells is CD-2 present on the surface of?

A

All T cells (and NK cells)

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11
Q

What kinds of T cells is CD-4 present on the surface of?

A

All T cells

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12
Q

What kinds of T cells is TCR present on the surface of?

A

All T cells

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13
Q

What kinds of T cells is CD-44 present on the surface of?

A

All T cells

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14
Q

What kinds of T cells is CD45RA present on the surface of?

A

found on naïve T cells

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15
Q

What kinds of T cells is CD45RO present on the surface of?

A

found on activated and memory T cells

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16
Q

What are the three main types of effector T cells?

A

(1) CD8 effector cells that are known as either cytotoxic T cells or CTLs, or even killer T cells.(2) T helper-1 type effector CD4+ T cell (3) T helper-2 type effector CD4+ T cellsThere are a couple of other types of effector T cells, but these are the three that are most important for this course.

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17
Q

What is the primary function of CD8 effector cells, known as CTLs?

A

to kill infected cells, resulting in premature termination of the replicative cycle of the pathogen. Think intracellular and viruses

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18
Q

CTLs produce several effector molecules (cytotoxins) that are responsible for their host cell killing function. Name them.

A

These are Fas ligand, perforin, granzymes, and granulysin.

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19
Q

CTLs also produce some important cytokines that are involved in development of immune responses. Name these.

A

LT and IFN-gamma

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20
Q

What is the primary function of CD4 effector cells?

A

The primary role of effector CD4 T cells is to supply the critical secondary activation stimuli that are needed to activate an antigen-specific B cell and to drive their differentiation. Both TH1 and TH2 cells have this function. TH1 cells also function to ‘classically’ activate macrophages, making them more phagocytic and more bacteriocidal.

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21
Q

What are the important effector molecules of CD4 effector cells?

A

CD40-ligand and the cytokines that they produce.

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22
Q

What cytokines do TH1 cells produce?

A

IFN-gamma, GM-CSF, TNF-alpha, LT, and IL-3

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23
Q

What cytokines do TH2 cells produce?

A

IL-4, IL-5, IL-10, IL-13, and TGF-beta

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24
Q

There are two additional CD4+ effector T cell types that you should know about, namely:

A

(1) Regulatory T cells (or Tregs): these cells’ function is to prevent activation of self-reactive T cells.(2) TH17 Cells: these cells induce production of neutrophil chematractants and antimicrobial peptides by several cell types.

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25
Q

A naïve T cell (CD4+ or CD8+) requires what two signals of activation?

A

(1) recognition of cognate antigenic determinant via the TCR, and (2) costimulation, in the form of B7 molecules on the APC binding to CD28 on the T cell.

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26
Q

What happens if a naive T cell receives both of these signals?

A

When these signals are received, the T cell begins to proliferate (driven by the autocrine growth factor, IL-2).Once the resulting daughter T cells have fully differentiated in effector cells, they move into inflamed tissues and sample peptide:MHC complexes. If they recognize their cognate peptide bound to an MHC molecule, they will perform their effector function. In the case of an effector CD8 T cell, that effector function is to limit the pathogen’s replicative cycle by killing the infected cell by initiating programmed cell death (or apoptosis). By killing the infected cell, they halt the replicative cycle of the pathogen and cause release of the pathogens that have accumulated inside the cell, making them susceptible to other immune responses (e.g. complement, antibodies/phagocytes, etc.)..

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27
Q

What is Perforin?

A

A primary effector molecules made by effector CD8+ T cells that is a membrane active molecule that inserts into host cell membranes as a multimeric complex (similar to membrane attack complex), forming pores in the cytoplasmic membrane of the cell.

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28
Q

What is Granulysin?

A

A primary effector molecules made by effector CD8+ T cells that is another membrane active molecule that can form pores in the cytoplasmic membrane of host cells. It also appears to have antimicrobial properties.

29
Q

What are Granzymes?

A

Primary effector molecules made by effector CD8+ T cells that are serine proteases that initiate the apoptotic pathway (programmed cell death) if they gain access to the host cell cytoplasm.When a CTL degranulates, it releases these three molecules. Perforin and granulysin create pores in the cytoplasmic membrane of the host cell, allowing granzymes to gain access to the cytoplasm of the cell (with help). Once perforin is in the cytoplasm, it initiates the caspase cascade that results in programmed cell death (apoptosis).

30
Q

What is the size of the pores created by Perforin and Granulysin?

A

16nm

31
Q

T or F. The size of the pores made by perforin and granulysin are large enough for granzymes to pass through.

A

F. They are too small

32
Q

So, how do the granzymes gain access to the host cell cytoplasm?

A

the current theory is that perforin-mediated pore formation signals the target cell to endocytose the affected membrane area for repair. The granzymes associate closely with the membrane and are brought along for the ride. Once there, they initiate the caspase cascade, resulting in apoptotic cell death. This mechanism is called ‘reparative endocytosis’

33
Q

Two other important effector molecules of CTLs (or effector CD8+ T cells) are:

A

Interferon (IFN)-gamma and Fas ligand.

34
Q

What does Interferon gamma do?

A

It is a cytokine that drives differentiation of TH0 T cells toward a TH1 phenotype. This is important because TH1 responses are critical for clearance of most intracellular infections

35
Q

What does Fas ligand do?

A

Fas ligand is a protein that can initiate programmed cell death by binding to Fas on the surface of host cells.

36
Q

How does Fas ligand work?

A
  1. A single copy of Fas ligand binds to three copies of Fas on the surface of a host cell. 2. When three copies of Fas are brought together by binding to Fas ligand, it brings their intracellular domains together and causes them to undergo conformational changes that make them a template for binding by adaptor proteins that have so-called “death domains”.3. These adaptor proteins recruit and activate caspase 8, which in turn cleaves caspase 3.4. Once caspase 3 has been activated, it cleaves a protein known as I-CAD (or inactivator of CAD). CAD stands for caspase activatable Dnase. Once I-CAD has beencleaved, it becomes active, it enters the host cell nucleus, and it destroys the host cell DNA by cutting it into small pieces.You should also be aware that Fas ligand expressed by CTLs is confined to the inside of their cytotoxic granules. It becomes exposed when the CTL degranulates.The combined action of Fas ligand and granzymes efficiently initiate the apoptotic pathway. You need to know that Fas ligand must bind to three copies of Fas, and that when this occurs it activates the caspase cascade that ultimately results in cleavage of I- CAD, resulting in activation of CAD. You also need to know that the cell is killed because CAD fragments the host cell DNA.
37
Q

T or F. All effector T cells only need a single activation signal.

A

T. Once an effector T cell recognizes its cognate peptide antigen bound to an appropriate MHC molecule, it will perform its effector function. Effector T cells do not require B7 costimulatory signaling.

38
Q

Can CTLs kill more than one infected host cell?

A

Yes, CTLs can regenerate their granule contents and continue to kill cells bearing their cognate determinant for their entire “lifespan”.CTLs will only kill cells that are presenting the CTL’s cognate peptide determinant bound to an MHC class I molecule. Uninfected cells will not be targeted for destruction.

39
Q

Adhesion molecule interactions are required for effector T cells to perform their effector functions. How do they work?

A

All interactions between effector T cells and other host cells are initiated by adhesion molecule interactions. In this slide you can see that the integrin LFA-1 expressed by the CTL binds to ICAM that is expressed on the host cell. This interaction brings the CTL in close enough proximity to the host cell to sample peptide:MHC complexes via their TCR. If the CTL does not recognize its cognate peptide, it releases and continues sampling peptide MHC complexes until it encounters its cognate peptide bound to an MHC class I molecule. Once this happens, it performs its effector function, resulting in apoptotic death of the host cell.

40
Q

How do CTLs release their granular contents so that they only affect the target cell and not surrounding cells?

A

CTLs have the ability to release their granule contents in a polarized fashion so that they kill their target cell, but not the uninfected neighbor cells.

41
Q

Which effector T cells can classically activate macrophages?

A

TH1 cells (via IFN-y)

42
Q

T or F. There are a number of non-viral pathogens (particularly bacteria) that are also well adapted for survival inside of host cells, and specifically macrophages.

A

T. These bacteria are referred to as “intracellular bacteria”

43
Q

What are some examples of intracellular bacteria?

A

Mycobacterium tuberculosis, Listeria monocytogenes, Salmonella typhi, Francisella tularensis, Burkholderia pseudomallei, and Yersinia pestis.fungus- Histoplasma capsulatumIntracellular bacteria are typically not killed by macrophages unless the macrophages are highly activated, and this requires TH1-mediated activation.

44
Q

When a TH1 CD4+ effector cell recognizes its cognate antigen bound to an MHC class II molecule on a macrophage, it will activate the macrophage by what supplying two signals?

A

(1) CD-40 ligand on the T cell binds to CD40 on the macrophage, and (2) the T cell will produce IFN-gamma that binds to IFN- gamma receptors of the macrophage.When this occurs, the macrophage becomes fully activated and will be more phagocytic, a better antigen presenting cell, and more bacteriocidal, and therefore better able to kill bacteria that it has taken up.

45
Q

What happens when a macrophage becomes fully ‘activated’ via CD40 and IFN-gamma binding with a TH1 cell?

A

it upregulates expression of MHC class I and MHC class II as well as B7 molecules, making it a better antigen presenting cell. It also upregulated oxygen intermediates and nitric oxide production, making it more bacteriocidal.

46
Q

What are some of the other functions of TH1 cells (6 things)?

A

1) TH1 cells also express Fas ligand and lymphotoxin (LT), enabling them to actually kill worn out macrophages that are chronically infected. This results in release of the pathogen so that fresh macrophages can take them up and destroy them.2) TH1 cells produce large amounts of IL-2, which is the autocrine growth factor for T cells. Production of IL-2 promotes T cell activation, increasing the number of effector T cells.3) TH1 cells produce IL-3 and GM-CSF. These cytokines induce macrophage differentiation in the bone marrow.4) TH1 cells produce TNF-alpha and lymphotoxin. These cytokines activate vascular endothelium, resulting in easier movement of macrophages from the circulation into inflammatory sites.5) TH1 cells produce CXCL2 (or MIP; macrophage inflammatory protein). CXCL2 is a macrophage chemotactic factor that promotes accumulation of macrophages at the site of infection.6) supplying of secondary activation signals to naïve B cells.

47
Q

Naive B cells require what two activation signals to become activated?

A

(1) recognition of their cognate antigenic determinant through their B cell receptor, and (2) activation stimuli from helper T cells that consist of CD40-ligand of the T cell binding to CD40 on the surface of the B cell, and cytokine signals produced by the helper T cell.

48
Q

Describe how B cell activation works.

A

When a B cell recognizes its cognate antigenic determinant, it endocytoses that antigen, processes any protein components, and they displays peptides derived from the antigen on MHC class II molecules (primarily) on its surface. When a helper T cell (either TH1 or TH2) recognizes its cognate peptide determinant bound to MHC class II molecules on the surface of of that B cell, it will perform its effector function: it will supply the CD40 ligand and cytokine signals, resulting in activation of the B cell.

49
Q

The cytokines produced by TH1 cells signal a developing B cell to undergo class switching to antibody isotypes that are strongly opsonizing (___ and ___) and are best for fighting ___ infections. TH2 cells produce cytokines that promote class switching to antibody isotypes that are weakly opsonizing (__, __, __, and __) and best for clearance of _____ infections.

A

TH1: IgG1 and IgG3; intracellularTH2: IgG2, IgG4, IgA, and IgE; extracellular

50
Q

Which intracellular bacteria can evade macrophages even after they have been activated?

A

Mycobacterium tuberculosis (MTb) and the fungus Histoplasma capsulatum

51
Q

How does the immune system prevent these types of pathogens from disseminating?

A

Granuloma formation essentially “walls-off” the pathogen, preventing dissemination. Think of granulomas in Chron’s and Sarcoidosis

52
Q

What are granulomas composed of?

A

Granulomas are composed primarily of macrophages, that often fuse to form giant multinuclear cells, and TH1 CD4 effector T cells around the periphery. The center of the granuloma often becomes necrotic when the cause of the granuloma is an infectious agent.TH1 cells are required for this immune mechanism. Patients that have a genetic immunodeficiency of either CD40 or CD40 ligand expression cannot fully activate their macrophages, and therefore, they cannot produce granulomas. These patients will often be diagnosed with systemic infection with an opportunistic species of Mycobacterium known as Mycobacterium intracellulare.

53
Q

What is the primary function of Tregs?

A

To prevent activation of self-reactive naïve T cells. Tregs have a limited TCR repertoire with specificities that are mostly limited to self determinants.

54
Q

What happens when a Treg recognizes a peptide:MHC complex on a host cell?

A

It usually is recognizing a self determinant.If a Treg recognizes its cognate determinant and also receives an additional signal (CTLA-4 on the Treg binding to B7 on the APC, it will begin to produce and secrete TGF-beta and IL-10. These two cytokines have anti-inflammatory properties that will act on any T cell that is also sampling peptides on that APC, making it less likely that the T cell will become activated.

55
Q

What do T helper type 17 (TH17) cells do?

A

They are a pro-inflammatory cell type that has important role in anti-microbial immunity at epithelial/mucosal barrier

56
Q

What cytokines do TH17 cells produce and what do they do?

A

IL-17 and IL-22, which stimulate epithelial cells to produce neutrophil chemotractants and anti-microbial proteins, respectively

57
Q

What is IL-2 produced by and what does it do?

A

produced by TH1 cells and CTLs (as well as by naïve T cells following activation), and it promotes proliferation of T cells, NK cell growth, and B cell growth and J-chain synthesis

58
Q

What is IFN-gamma produced by and what does it do?

A

produced by TH1 cells and CTLs. 1) Inhibits TH2 cell growth (or stimulates THI formation)2) Activates NK cells and macrophages (classically)3) It is also involved in the interferon response that makes host cells less susceptible to virus infection.4) promotes class switching to IgG2 (could be wrong)

59
Q

What is lymphotoxin (or LT or TNF-β) produced by and what does it do?

A

produced by TH1 T cells and by CTLs and 1) provides activation stimuli for macrophages, encouraging nitric oxide production.2) Inhibits B and T cell growth3) Activates neutrophils

60
Q

What is IL-4 produced by and what does it do?

A

is produced by TH2 T cells and it 1)supports growth and survival of TH2 T cells. 2) promotes B cell activation and class switching to IgE. 3) alternatively activates macrophages 4) activates mast cells

61
Q

What is IL-5 produced by and what does it do?

A

is produced by TH2 cells and it is 1) the primary driving signal for class switching of B cells to IgA. 2) It also promotes growth/differentiation of eosinophils

62
Q

What is IL-10 produced by and what does it do?

A

produced by TH2 T cells and Tregs (and alternative macrophages), and it 1) has anti-inflammatory effects that result in an inhibition of cytokine release by classical macrophages, 2) promotes TH2 cell activation.3) promotes MHC class II expression on B cells

63
Q

What is IL-3 produced by and what does it do?

A

produced by both TH1 and TH2 cells and CTLs and serves as a growth factor for hematopoietic progenitor cells in the bone marrow (similar effects to GM-CSF).

64
Q

What is TNF-alpha produced by and what does it do?

A

produced by both TH1 and TH2 cells and CTLs and 1) serves as an activation signal for classical macrophages (induced NO production)2) as a activator of vascular endothelium

65
Q

What is granulocyte-macrophage colony-stimulating factor (GMCSF) produced by and what does it do?

A

produced by both TH1 and TH2 cells and CTLs and 1) serves as a growth factor for hematopoietic progenitor cells in the bone marrow resulting in increased production of macrophages and granulocytes.

66
Q

What is Transforming growth factor (TGF)-beta produced by and what does it do?

A

an anti-inflammatory cytokine produced by Tregs (primarily). 1) Most important function is to prevent activation of self-reactive T cells.2) Inhibits B cell growth and IgA class switching3) inhibits classical macrophage activation

67
Q

What is IL-17 produced by and what does it do?

A

produced primarily by TH17 cells and serves 1) as a signal for induction of neutrophil chemokines by endothelial cells.2) stimulates fibroblasts and epithelial cells to secrete chemokines

68
Q

What is IL-22 produced by and what does it do?

A

produced primarily by TH17 cells and serves as a signal for induction of antimicrobial peptide production by endothelial cells.

69
Q

How does cytokine signaling work?

A

Cytokine receptors are typically heterodimers. The intracellular domain of each monomer are associated with Janus kinase proteins known as JAKs.When the JAKS are brought in close proximity, due to cytokine binding, they become enzymatically active and phosphorylate the receptor.Once phosphorylated, the JAK receptors now become a ligand for transcription factors known as STATs. Once they bind, the STATs are phosphorylated by the JAKs.Once phosphorylated, the STATs dimerize and move into the nucleus where they initiate transcription of the cytokine gene.

STEP Physiology (68 decks)

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