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Immunology Exam III > Handout 11: Differentiation and Functions of CD8+ T cells > Flashcards

Handout 11: Differentiation and Functions of CD8+ T cells Flashcards

0
Q

What is the typical life cycle of T lymphocyte in terms of its state of maturation?

A

pre-T cell–>Selection of T cells with appropriately rearranged receptors for Ag–>Naive T cells–>Encounter with Ag-bearing DC leads to activation and functional polarisation to effector or memory T cell–>carry out effector functions–>Memory T cell (or can go directly from Naive T cell to memory T cell)

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1
Q

What is the typical life cycle of T lymphocyte in terms of its site of maturation?

A

Bone–>Thymus–>Lymph node–>Peripheral tissue–> lymph node
OR
Bone–>Thymus–>Lymph node

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2
Q

T cells are generated from precursors in the ____ which then migrate to the ____

A

bone marrow, thymus

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3
Q

Like B cells in the bone marrow, T cells in the thymus also engage in what to generate a receptor for Ag?

A

rearrangement of genes

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4
Q

After rearrangement of genes takes place, like B cells, T cells then leave to populate ____ in a ______,_____ state

A

Lymph nodes, naive, immature

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5
Q

What key properties are used to select which T cells migrate into the lymph nodes from the thymus?

A
  1. Functional rearrangement and expression of their surface receptors for Ag
  2. Reduced or absent tendency to recognize self Ag (and thus avoid autoimmunity)
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6
Q

How do naive or immature T cells first become activated in the lymph node?

A

via Ags presented to them as short peptides bound to MHC molecules on the surface of APCs.

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7
Q

Only one type of cell is capable of activating naive T cells. What cell is this?

A

Dendritic cell

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8
Q

Aside from presentation of Ag to naive T cell, what other events are involved in activating the T cell? What is the result?

A

A series of coordinated signals involving the interaction on the DC and T cell surface and secretion of cytokines by the DC

Result: activation of T cell and functional polarization

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9
Q

What is functional polarization?

A

Means that the T cell takes on a particular set of tasks that promote the adaptive immune response (ex: organizing B cell responses)

Also called effector or regulatory functions, depending on nature

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10
Q

T cell population: T lymphocytes
Marker:
Typical percent in blood:
Additional info:

A

Marker: CD3 (TCR)
Typical percent in blood: 100% of T cells*
Additional info: All T cells are thymus derived

  • 70% of all lymphocytes in the blood. B cells comprise remaining 30% of blood lymphocytes
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11
Q

T cell population: Helper T lymphocytes (Th)
Marker:
Typical percent in blood:
Additional info:

A

Marker: CD4
Typical percent in blood: 66% Of T cells
Additional info: Are class II MHC restricted

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12
Q

T cell population:Cytotoxic T lymphocytes (CTLs)
Marker:
Typical percent in blood:
Additional info:

A

Marker: CD8
Typical percent in blood: 33% of T cells
Additional info: Class I MHC restricted

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13
Q

How is activation of CD8+ T cells similar to activation of CD4+ T cells?

A

They are both activated in LNs by dendritic cells loaded with Ags

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14
Q
  1. CTLs recognize ____.
  2. Activated CD8+ cells then ____ and ____ the LN.
  3. CD8+ T cells are activated by mechanisms that involves ____ of Ags to _____
A
  1. class I MHC-associated peptides
  2. proliferate, leave
  3. cross-presentation; CD8+ T cells
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15
Q

How are extracellular Ags that are processed and presented within class II MHC also presented in association with class I MHC?

A

via cross presentation–some viral Ags are released from phagosome in cytoplasm of DC and then presented within class I MHC

The same cross presenting APC may display microbial peptides within class II MHC for CD4+ helper T cells

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16
Q

What is the sequence of events in Ag cross presentation with class I MHC?

A
  1. Ag capture: Infected cells and viral Ags are picked up by host APC
  2. Cross presentation: viral Ag released from phagosome in cytoplasm of DC presented within class I MHC
  3. T cell response
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17
Q

How do CD4+ T cells help activate CTLs?

A
  1. CD4+ T helper cells produce cytokines that stimulate CTL differentiation
  2. CD4+ T helper cells enhance ability of APCs to stimulate CTL differentiation
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18
Q

How are CTLs activated without the use of T helper cells?

A

CD8+ T cells recognize Ag and costimulators on professional APC which leads to CTL differentiation without helper T cells

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19
Q

CD8+ T cells are _______

A

Class I MHC restricted

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20
Q

What is the process by which CD8+ T lymphocytes are activated and differentiated?

A
  1. Naive CD8+ T cells recognize peptide Ag presented by DCs in LNs
  2. CD8+ T cells are stimulated to proliferate and differentiate into CTLs and memory cells
  3. Differentiated CD8+ CTLs enter circulation and migrate to site of Ag
  4. CD8+ CTLs recognize Ag in tissues and respond by killing target cells where Ag is produced
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21
Q

The naive CD8+ T cells, like all naive T cells are activated by Ags presented by ___

A

Dendritic cells

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22
Q

Ags that are recognized by CD8+ T cells usually come from what?

A

viruses or tumors derived from a variety of cell types

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23
Q

What is cross presentation important for?

A

Important for Ag presentation by professional APCs within class I MHC

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24
Q

After cross presentation, how are Ags presented in class I MHC molecules?

A

Exogenous Ags derived from ingested infected cells, tumor cells, or their proteins are transferred into the cytosol for processing, loading, and presentation in class I MHC

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25
Q

What is the first signal of CTL activation? What is the second signal?

A

1st signal: Naive CD8+ cells recognize Ags

2nd signal: CD28-CD80 costimulation which proliferates and differentiates into effector CTLs

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26
Q

How do activated CTLs kill other cells?

A

They release granules called lysosomes that contain perforin and granzymes to kill other cells

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27
Q

What cytokine do CTLs secrete? What is this cytokine’s function?

A

Activated CTLs secrete IFN-gamma which potently activates macrophages

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28
Q

CTL differentiation involves what transcription factor? What other cell differentiation is this transcription factor involved in?

A

T-bet transcription factor; also used by Th1 cell activation

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29
Q

What is the function of T-bet transcription factor?

A

Regulates transcription of genes encoding perforin, granzymes, and IFN-gamma

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30
Q

What is the third signal that enhances CTL differentiation? When is this third signal required?

A

CD4+ helper T cells provide the 3rd signal. Required for CD8+ T cell responses when relatively weak innate immune reactions are evoked by latent viral infections, organ transplants, and tumors

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31
Q

Is CD4+ helper T cells more important for generation of CD8+ memory T cells or for differenitation of naive CD8+ T cells into effector CTLs?

A

CD4+ helper T cells MORE important for CD8+ memory T cells

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32
Q

When does licensing of the APC occur?

A

When the CD4+ T cell recognizes Ag presented by an MHC class II+ APC and delivers activating signals through CD80/CD86 and CD40

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33
Q

What do activated CD4+ Th cells express? What does that bind to?

A

CD40L which may bind to CD40 on Ag loaded DCs

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34
Q

What upregulates the expression of CD80/CD86 on professional APC? Why is this upregulation necessary?

A

CD40-CD40L; this upregulation of CD80/CD86 makes them more efficient at stimulating the deifferentiation of CD8+ T cells

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35
Q

CD8+ T cell differentiation _____(does or does not?) require that CD4+ and CD8+ T cells should be in contact with the APC at the same time.

A

Does not

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36
Q

Which cytokine promotes the proliferation and differentiation of CD8+ T cells into CTLs and memory cells? Which subunit of this receptor is highly expressed by CD8+ T cells after activation?

A

IL-2; alpha subunit of IL-2R is highly expressed

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37
Q

IL-2R shares a common receptor component with two other cytokines. What are these two cytokines and what is the subunit they have in common?

A

IL-15 and IL-21. They share the gamma chain

38
Q

Which cytokines stimulate the differentiation of naive CD8+ T cells into effector CTLs?

A

IL-12 and type I IFNs

39
Q

Naive CD8 T cells proliferate in response to ____ and ___ signals, but require ____ or ____for survival and development of optimal effector functions

A

TCR, CD28

IL-12, type I IFN

40
Q

What types of cells produce IL-15? What is the function of this cytokine?

A

DCs and tissue macrophages produce IL-15 which is important for the survival of memory CD8+ T cells. Mice lacking IL-15 show loss of memory CD8+ T cells

41
Q

How does IL-21 play a role in CTL activation?

A

IL-21 produced by activated CD4+ T cells induces CD8+ T cell memory and prevents CD8+ T cell exhaustion

42
Q

What cytokine is known as a T cell growth factor? What does it do?

A

IL-2; leads to T lymphocyte activation and proliferation

43
Q

The autocrine loop operates through which cytokine (15kDa)?

A

IL-2

44
Q

Functions of IL-2

A

activation of T cells resulting in upregulation of IL-2 and IL2-R
activation of nearby CD8+ T cells in paracrine fashion

45
Q

IL-2 shares a common receptor components with which other cytokines? What are the common receptor it shares?

A

Shares the gamma chain receptor component with:

IL-4, IL-7, IL-9, IL-15, and IL-21

46
Q

What cells produce the IL-12 cytokine? What is its function in terms of T cell differentiation?

A

DCs and macrophages; It induces naive CD4 T cells to differentiate into Th1 effector cells

47
Q

The balance of what two cytokines determines whether CD4 T cells become Th1 or Th2 cells?

A

IL-12 and IL-4

48
Q

IL-12 promotes CD4+T and CD8+ T cells to produce what two pro-inflammatory cytokines?

A

IFN-gamma and TNF-beta

49
Q

Which cytokine (IL-12 or IFN) are more effective in controlling tumor and maintain high numbers and function of CD8+ T cells?

A

IL-12

50
Q

Which cytokine prevents CD8+ T cell exhaustion and also activates NK cell?

A

IL-12

51
Q

What is the primary source of IL-15?

A

Activated tissue macrophages and mature DCs

52
Q

IL-15 shares similar biologic properties with which cytokine?

A

IL-2

They share common receptor (R) signaling components

53
Q

What are the functions of IL-15?

A

T-cell growth factor that proliferates CTL cells
potent chemoattractant for T cells isolated from human blood
Proliferation of memory CD4+ and CD8+ and naive CD8+ T cells
costimulates innate immune IFN-gamma production

54
Q

What releases IFN-gamma

A

Th1 cells, CTLs, activated NK cells

55
Q

What is the structure of IFN-gamma?

A

Homodimer composed of subunits of approximately 25 kDa

56
Q

What are the functions of IFN-gamma?

A

activates macrophages–increasing metabolic, phagocytic, and killing activity
increases MHC class I molecule expression on different cells and induces expression of MHC class II molecules on professional APCs
promotes development of Th1 cells and B cell differentiation and favors IgG production and inhibits IgE production

57
Q

What is the importance of IFN-gamma increasing MHC class I expression on various cells and inducing MHC class II expression on APCs?

A

Important in antiviral protection, since it upregulates Ag presentation of viral targets by infected cells

58
Q

In acute infections, how are infected cells eliminated?

A

CD8+ T cells differentiate into CTLs that eliminate the infected cells
(Effector and memory CTL secrete cytokines, proliferate and kill target cells)

59
Q

How are viral Ags presented to CD8+ T cells?

A

DCs present the viral Ags to CD8+ T cells which initiates clonal expansion and differentiation into CTLs

60
Q

What are the cytokines that activated CTLs secrete?

A

Secrete pro-inflammatory TNF-beta, IFN-gamma, and cytotoxic perforin and granzymes

61
Q

After the virus has been cleared, what phase does the CD8+ T cells undergo?

A

Undergoes extensive contraction phase mediated by apoptosis

62
Q

What are the stages of CD8+ life cycle?

A

DC presents viral Ag to CD8+ T cell
Clonal expansion and differentiation into CTLs
Contraction and apoptosis
Memory CD8+ T cells

63
Q

What is exhaustion?

A

Where the response of CD8+ T cells is gradually extinguished during chronic viral infections
Exhaustion suppresses immune response in chronic viral infection

64
Q

What cytokines are reduced in expression during exhaustion? What is upregulated?

A

Reduced production of IFN-gamma

Increased expression of PD-1 inhibitory receptor (Inhibitory signals from PD-1 blocks activation of CTLs)

65
Q

PD-1 mediated T cell exhaustion contributes to chronicity of what diseases?

A

HIV

hepatitis C virus (HCV)

66
Q

Anti-PD-1 Abs are used to treat what?

A

It is effective against immuno-therapy of tumors

67
Q

For CTL mediated cytotoxicity to occur, what two major events need to occur?

A

TCR dependent recogition

Induction of apopotosis in target cells

68
Q

In CTL mediated cytotoxicity, TCR recognizes specific Ags within what class of molecules?

A

Class I MHC molecules

69
Q

In CTL mediated cytotoxicity, what is the purpose of TCR recognition of Ag within class I MHC?

A

It brings the CTL and the target cell in close contact which results in formation of the immunologic synapse

70
Q

What is the function of the immunologic synapse?

A

It ensures that normal bystander cells are not injured by CTLs reacting against infected cells
Perforin and Granzymes which perform the killing are secreted into the synapse and cannot diffuse to other nearby cells

71
Q

When CTLs kill target cells, do the CTLs themselves get injured too?

A

No, they are not injured

72
Q

Sequence of events of CTL mediated cytotoxicity

A

Ag recognition and immune synapse formation–>granule exocytosis–>Detachment of CTL–>Target cell death

73
Q

What are the two major mechanisms by which CTLs kill target cells?

A
  1. Perforin/granzyme mediated cell killing

2. Fas/FasL mediated cell killing

74
Q

How does perforin/granzyme mediated cell killing work?

A

Complexes of perforin and granzymes are released from the CTL by granule exocytosis and enter target cells. Granzymes are delivered into cytoplasm of target cells by perforin-dependent mechanism which induce apoptosis

CTL releases granule contents into immune synapse. Perforin induces uptake of granzymes into target cell endosome and release into cytosol, activating caspases

75
Q

How does Fas/FasL-mediated cell killing work?

A

FasL is expressed on activated CTLs which interacts with Fas on surface of target cells and induces apoptosis

76
Q

Granzymes A, B, and C are ____ proteases

A

serine

77
Q

Which granzyme is required for CTL cytotoxicity in vivo?

A

Granzyme B

78
Q

Perforin is a membrane-perturbing molecule that is homologous to what other protein?

A

C9 complement protein

79
Q

Granules (granzyme and perforin) also contain a sulfated proteoglycan called _____. What is its function?

A

serglycin

serves to assemble a complex containing granzymes and perforin

80
Q

What happens after perforin is inserted into the target cell membrane?

A

It elicits a membrane repair process which leads to internalization of both the perforin and granzymes into endosomes

81
Q

How does granzyme B trigger apoptosis?

A

Granzyme B activates caspase-3 which triggers apoptosis

82
Q

How does FasL-induced apoptosis begin?

A

Binding of FasL to Fas recruits procaspase-8 through the FADD adaptor which concerts it into the active enzyme caspase-8

83
Q

What does caspase-8 do?

A

In type-1 cells like thymocytes, caspase-8 directly cleaves caspase-3
In type-2 cells like virus infected hepatocytes, caspase-8 cleaves Bid and truncated Bid stimulates release of cytochrome c from mitochondria

84
Q

What does cytochrome c along with apoptotic peptide activating factor 1 (Apaf-1) and ATP do?

A

activates caspase 9 which in turn activates caspase-3

85
Q

What is ICAD (inhibitor of caspase-activated DNase [CAD])?

A

One of the substrates of caspase-3

86
Q

How is CAD activated? What is the result of activating CAD?

A

Cleavage of ICAD by caspase-3 activates CAD which causes DNA degradation in nuclei

87
Q

FasL-induced apoptosis summary

A

FasL-Fas binding recruits pro-caspase-8–>caspase8–>cleaves caspase-3 or Bid–>Bid releases cytochrome c–>cytochrome c and Apaf-1 and ATP–>activated caspase-9–>caspase-3 activated–>activated CAD–>DNA degradation

88
Q

How are CD4+ T helper cells involved in CD8+ T cell memory response

A

CD4+ T helper cells help stimulate both dendritic cells and CD8+ T cells to maintain a CD8+ T cell memory
response

CD4 T helper stimulates DC and CD8+ effector cells OR
Naive CD8+–>Memory CD8+–>Effector CD8+

89
Q

CD8+ CTLs in host defense (HIV)

A

Naive CD8+–>Memory

90
Q

What are the functions of Effector CD8+ cells

A

Produces cytokines: IFN-gamma, TNF-alpha
Produces chemokines: MIP-1alpha/Beta and RANTES
Lysis of infected cells using Perforin, granzymes & Fas/FasL

91
Q

For what kind of microbes do CD4+ T cells cooperate with CD8+ T cells?

A

defense against intracellular microbes

92
Q

This type of intracellular bacteria are phagocytotized by macrophages and may survive in phagosomes and escape into cytoplasm

A

L. monocytogenes

93
Q

What is the role of CD4+ T cells vs. the role of CD8+ T cells in CTL host defense?

A

CD4+ T cells respond to class II MHC associated peptide Ag derived from intravesicular bacteria and produce IFN-gamma and IL-2 (kills bacteria in phagolysosome)

CD8+ T cells respond to class I-associated peptides derived from cytosolic Ags and kill infected cells

Immunology Exam III (5 decks)

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