Lecture 11: Differentiation and Functions of CD8+ T cells

Question 1

CD4 is on what percentage of T cells

Answer 1

66%

Question 2

CD8 is on what percentage of T cells

Answer 2

33%

Question 3

T cells make up ___ % of all the lymphocytes in the blood. While B cells comprise the remaining ___% of blood lymphocytes

Answer 3

• T cells: 70%
• B cells: 30%

Question 4

CD4 cells are what MHC class restricted

Answer 4

Class-II

Question 5

CD8 cells are what MHC-class restricted

Answer 5

Class-I MHC restricted

Question 6

Rearrangement of genes of the T cell occurs where in the body

Answer 6

the thymus (this generates a receptor for Ag)

Question 7

Functional polarization means that the T cell takes on a particular set of tasks that promote the

Answer 7

adaptive immune response. These are often called effector or regulatory functions, depending on their nature

Question 8

Naive CD8+ cells recognize Ags (signal 1) and proliferate and differentiate in to effector CTLs upon ______ costimulaiton (signal 2)

Answer 8

CD28-CD80

Question 9

activated CTLs contain numerous granules called lysosomes that contain _____ and _____ used by the cells to kill other cells

Answer 9

perforin and granzymes

Question 10

Activated CTLs secrete mostly what cytokine

Answer 10

• Mostly IFN-gamma (which potently activate macrophages)

Question 11

similar to activation of Th1 cells, the molecular events in CTL differentiation involve transcription factor

Answer 11

T-bet

Question 12

T-bet regulates transcription of genes encoding for ____, ___, and ____ in CD8 cells

Answer 12

• Perforin
• Granzymes
• IFN-gamma

Question 13

• What is cross presentation

Answer 13

• Dendritic cells canpresent class II MHC-associated peptides generated in the vesicles to CD4+ helper T cells, which are often required to induce full responses of CD8+ cells
• involves the fusion of phagosomes containing the ingested antigens with the ER. Ingested proteins are then translocated from the ER to the cytosol by poorly defined pathways that are likey involved in presentation of proteins degraded in the ER

Question 14

The full activation of naive CD8+ T cells and their differentiation into functional CTLs and memory cells may require the participation of ______

Answer 14

• CD4+ helper cells
  
  • provide second signal for CD8+ T cells
    
    • secrete cytokines that stimulate differentiation of CD8+ cells
    • express CD40L which may bind to CD40 on atigen-loaded dednritic cells. This interaction activates the APCs ot make them more efficient at stimulating the differentiation of CD8+ T cells, in part by inducing the expression of costimulators. This process has been termed licensing of APCs
  • There is evidence that CD4+ helper cells are more important for the generation fo CD8+ memory T cells than the differentiation of naive CD8+ T cells into effector CTLs

Question 15

Mechanism of APC licensing

Answer 15

• Licensing of the APC occurs when the CD4+ T cell recognizes Ag presented by an MHC class II APC and delivers activating signals through CD80/CD86 and CD40
• CD40-CD40L interaction upregulates expression of CD80/CD86 on professional APCs which makes them more efficient at stimulating the differentiation of CD8+ T cells
• (does not require CD4+ and CD8+ T cells to be in contact with APC at the same time)

Question 16

CD4+ helper T cells are required for CD8+ T cell responses when ______ innate immune reactions are evoked by

Answer 16

• Relatively weak innate immune responses
• latent viral infections, organ transplants, and tumors

Question 17

CD4+ helper t cells provide signal ___ in form of cytokines which enhance activation of CTLs

Answer 17

3

Question 18

What cytokines contribute to the differentiation of CD8+ T cells and the maintenance of effector and memory cells of this lineage

Answer 18

• IL-2
  
  • promotes proliferation and differentiation of CD8+ T cells into CTLs and memory cells.
  • CD8+ cells express the beta and gamma chains of the IL-2 receptor and may express high levels of the alpha chain after activation
• IL-12 & type I IFNs
  
  • stimulate the differentiation of naive CD8+ T cells into effector CTLs
  • Naive CD8 t cells proliferate in response to TCR and CD28 signals, but require IL-12 or type I IFN for survival and development of optimal effector functions
• IL-15
  
  • important for survival of memory CD8+ cells
  • may be produced by many cell types, including dendritic cells and tissue macrophages
• IL-21
  
  • produced by activaed CD4+ T cells
  • plays a role in the induction of CD8+ T cell memory and the prevention of CD8+ T cell exhaustion

Question 19

IL-2R shares a common receptor component (the gamma chain) with what other cytokines

Answer 19

• IL-4, IL-7, IL-9, IL-15, and IL-21

Question 20

Ligands of Type I cytokine (hemopoietin) receptors

Answer 20

• IL-2
• IL-3
• IL-4
• IL-5
• IL-6
• IL-7
• IL-9
• IL-11
• IL-12
• IL-13
• IL-15
• IL-21
• IL-23
• GM-CSF
• G-CSF

Question 21

Ligands of IL-1 receptor family

Answer 21

• IL-1
• IL-18
• IL33

Question 22

Ligands of Type II cytokine receptors

Answer 22

• IFN-alpha/beta
• IFN-gamma
• IL-10
• IL-22

Question 23

Ligands of seven transmembrane G-protein coupled receptors

Answer 23

Chemokines

Question 24

Local release of IL-2 can lead to activation of nearby CD8+ T cells in a ____ fashion

Answer 24

paracrine

Question 25

IFN-gamma is a ____ composed of subunits of approximately 25kDa

Answer 25

Homodimer

Question 26

IFN-gamma is released by ___ cells and \_\_\_, as well as by activated \_\_\_\_\_

Answer 26

Th1 cells, CTLs, as well as by activated NK cells

Question 27

IL-12 is a key cytokine is produced by activated

Answer 27

DCs and Macrophages

Question 28

IL-12 has a profound effect of inducing naive CD4 T cells to differentiate into \_\_\_\_\_\_

Answer 28

Th1 effector cells

Question 29

The balance of IL-12 and IL-4 during naive CD4 T cell activation thus determines whether these cells become _____ or \_\_\_\_

Answer 29

Th1 or Th2

Question 30

IL-12 thus promotes production fo the pro-inlammatory cytokines ____ and ____ by CD4+ and CD8+ T cells

Answer 30

IFN-gamma and TNF-beta

Question 31

IL-12 simulated CD8+ T cells are more effective in controlling tumor and they maintain

Answer 31

high numbers and function as compared to type I IFNs-stimulated cells

Question 32

IL-12 assists in prevention of CD8+ T cells \_\_\_\_

Answer 32

exhaustion

Question 33

Activated CTLs secrete pro-inflammatory

Answer 33

TNF-beta, IFN-gamma and cyotoxic Perforin and granzymes

Question 34

exhausted CD8+ T cells show reduced production of IFN-gamma and increased expression of \_\_\_\_

Answer 34

PD-1 inhibitory receptor

Question 35

PD-1 mediated T cell exhaustion may contribute to the chronicity of

Answer 35

HIV and hepatitis C virus (HCV)

Question 36

Anti-PD-1 Abs are effective in the

Answer 36

immuno-therapy of tumors

Question 37

Perforin and granzymes are secreted by CTLs into the ____ and perform the killing and cannot diffuse to other nearby cells

Answer 37

Synapse

Question 38

What are the two mechanisms by which CTLs kill target cells

Answer 38

* Complexes of perforin and granzymes are released from the CTL by granule exocytosis and enter target cells. The granzymes are delivered into the cytoplasm of the target cells by a perforin-dependent mechanism, and they induce apoptosis * The FasL is expressed on activated CTLs, engages Fas on the surface of target cells, and induces apoptosis

Question 39

There are Granzymes A, B, and C, which are serine proteases. But which one is the only one to be required for CTL cytotoxicity in vivo

Answer 39

Granzyme B

Question 40

Perforin is a membrane-perturbing molecule that is homologous to the ____ complement protein

Answer 40

C9

Question 41

CTL granules contain a sulfated proteoglycan ____ which serves to assemble a complex containing granzymes and perforin

Answer 41

Serglycin

Question 42

When in the target cell, granzyme B activates _____ , that triggers apoptosis

Answer 42

Caspase-3

Question 43

Explain Fas-FasL-mediated apoptosis

Answer 43

* Binding of FasL to Fas recruits Procaspase-8 thourhg the FADD adaptor converts it into the active enzyme caspase-8 * in type-I cells such as thymocytes, caspase-8 can directly cleave caspase-3 * In type-II cells such as virus-infected hepatocytes, caspase-8 cleaves Bid and the truncated Bid stimulates the release of cytochrome c from mitochondria * cytochrome c, together with Apaf-1 (apoptotic peptidase activating factor 1) and ATP then activates caspase-9 which in turn then activates caspase-3 * Caspase-3 activates CAD (caspase-activated DNase) via degradation of ICAD (inhibitor of CAD) * Activated CAD causes DNA degradation in nuclei

Question 44

Viruses can enter the cells by two ways. explain

Answer 44

* Some virsuses can infect cells directly, leading to replicaiton of virus inside the cell. During this process, some of the viral proteins will be degraded into peptide fragments, which will be presented on MHC class I molecules to CD8+ cells * APCs, such as DCs can also take up viral particles or remnants of virally-infected cells * during processing by professional APCs, viral peptides can be presented on MHC class I molcules via the **cross-presentation pathway**