T-cell Effector Mechanisms

Question 1

What is an armed effector T cell?

Answer 1

A fully differentiated cell that is ready to perform its effector function. Does not require co-stimulation to perform its function. Express an array of adhesion molecules that direct them to appropriate tissues.

Question 2

What are the 3 main types of effector T cells?

Answer 2

effector CD8 (CTLs or killer T cells)
TH1 effector CD4
TH2 effector CD4

Question 3

What is L-selectin? What does it bind to? What effector cell has no L-selectin?

Answer 3

Expressed on the surface of naive CD4 and CD8 T cells. Binds to GLYCAM-1 and CD34 adhesion molecules on surface of endothelial cells that line the high epithelial venules on secondary lymphoid tissues. Only cells expressing L-selectin can enter these tissues. CD4 effector cells need to cycle through secondary lymphoid tissues to serve as secondary activators of antigen-specific B cells.

It is not found on effector CD8 T cells because they have no positive role in secondary lymphoid tissues, where they would have a destructive function, killing any APC presenting their cognate peptide on MHC molecules.

Question 4

What is VLA-4? What does it bind to?

Answer 4

It is upregulated on effector T cells, and is an integrin receptor that binds to VCAM-1 expressed on activated endothelial cells. This binding facilitates the movement of the effector cell across the vascular endothelium to an inflammatory site.

Question 5

What is CD45RA? What is CD45RO?

Answer 5

CD45RA: marker on naive T cells. CD45RO: marker on activated and memory T cells.

Question 6

What is the primary role of CD8 effector cells? How do they fulfill this role?

Answer 6

To kill infected cells, resulting in premature termination of replicative cycle of pathogen. They use Fas-L, perforin, granzymes, and granulysin.

Question 7

What is the primary role of effector CD4 cells (both types)? How do they fulfill this role?

Answer 7

To supply critical secondary activation signal to activate antigen-specific B cell and drive their differentiation. TH1 cells also activate macrophages, making them more phagocytic and bactericidal.

Question 8

What are the two signals of activation required by a naive T cell (CD4 or CD8)?

Answer 8

(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.

Question 9

What are perforin, granzymes, and granulysin?

Answer 9

Perforin - aids in delivering contents of granules into cytoplasm of target cell

Granzymes - serine proteases, which activate apoptosis once in the cytoplasm of the target cell

Granulysin - has antimicrobial actions, and can induce apoptosis

Remember: repairative endocytosis mechanism because pores not large enough for granzymes to get through

Question 10

What are two important effector molecules of CTLs (not including perforin, granzymes, and granulysin)?

Answer 10

IFN-gamma: cytokine that drives differentiation of TH0 T cells to TH1 phenotype, critical for intracellular pathogens

Fas-L: protein that can initiate programmed cell death by binding to Fas on surface of host cells

Question 11

What is the Fas-L MOA?

Answer 11

Brings together and binds three copies of Fas on surface of host cell - this brings their IC domains together and causes them to undergo conformational changes, making them a template for binding adaptor proteins with death domains that activate caspase 8, which cleaves caspase 3.

Question 12

Do effector T cells require B7 co-stimulatory signalling? What does the CDL-host cell interaction consist of?

Answer 12

CTL’s do not need B7 co-stimulation, and can kill many infected host cells - it will only kill cells presenting its cognate determinant.

The integrin LFA-1 on the CTL binds to ICAM on the host cell, bringing the two cells close enough together for the host cell to sample MHC peptide via its TCR. It simply releases and continues on until it encounters its MHC and initiates apoptosis of the infected cell.

Note: because of this process, the CTL is able to polarize itself and position its granules so they only impact the targeted cell when they are released (not neighboring cells).

Question 13

How do TH1 cells activate macrophages?

Answer 13

IC bacteria are typically not killed by macrophages unless the macros are highly activated - this requires TH1-mediated activation.

2 signals when TH1 CD4 effector cell recognizes cognate antigen on MHC class II on macro: 1) CD-40 ligand on the T cell binds to CD40 on the macro, 2) T cell produces IFN-gamma, which binds to IFN-gamma receptors on the macro.

The macro becomes fully activated and will be more phagocytic, a better APC, and more bactericidal.

Question 14

What is upregulated on and in activated macrophages?

Answer 14

MHC class I and MHC class II, as well as B7, making it a better APC. It also upregulates oxygen intermediates and NO production to make it more bactericidal.

Question 15

What is the most important function of CD4 effector T cells?

Answer 15

Supplying of secondary activation signals to naive B cells.

Question 16

What activation signals are required by B cells to become activated?

Answer 16

1) Recognition of their cognate antigenic determinant through their B cell receptor, and 2) CD40-CD40, and cytokine signals from helper T cells.

These helper T cells recognize the B cells based on their cognate determinant bound to MHC molecules on their surface.

Question 17

What class switching is produced by TH1? What about TH2?

Answer 17

TH1: IgG1 and IgG3 (strongly opsonizing)

TH2: IgG2, IgG4, IgA, and IgE (weakly opsonizing)

Question 18

When do granulomas form? What is their basic structure and purpose?

Answer 18

Form when microbe resists destruction by macrophages. Function is to prevent dissemination of the microbe.

Composed primarily of macrophages, often fused to form giant multinuclear cells, and TH1 CD4 effector T cells around the periphery.

Question 19

What deficiency would make a patient unable to make granulomas?

Answer 19

Genetic immunodeficiency of CD40 or CD40 ligand expression (because they cannot fully activate their macros).

Question 20

What is the effector role of Tregs and how do they complete it?

Answer 20

Suppression of autoreactive T cells - if they recognize their cognate determinant and receive an additional signal (CTLA-4 on Treg binding to B7 on APC), they begin to produce and secrete TGF-beta and IL-10 (anti-inflammatories, decreasing likelihood of activation of any T cells also sampling peptides on that APC).

Question 21

What do Tregs release?

Answer 21

IL-17: stimulates epithelial cells to produce neutrophil chemoattractants

IL-22: stimulates epi cells to produce anti-microbial proteins

Question 22

What is IL-2?

Answer 22

Produced by TH1 cells, CTLs, and naive T cells (following activation), and it promotes proliferation of T cells.

Question 23

What is IFN-gamma?

Answer 23

Produced by TH1 cells and CTLs - required for macro and NK cell activation. Also involved in interferon response that makes host less susceptible to viral infection.

Question 24

What is lymphotoxin?

Answer 24

LT or TNF-beta: produced by TH1 cells and CTLs, and provides activation stimuli for macros, encouraging nitric oxide production

Question 25

What is IL-4?

Answer 25

Produced by TH2 cells and supports their growth and survival. Also promotes class switching to IgE.

Question 26

What is IL-5?

Answer 26

Produced by TH2 cells and is primary driving signal for class switching of B cells to IgA (also promotes growth and differentiation of eosinophils)

Question 27

What is IL-10?

Answer 27

Produced by TH2 cells and Tregs, and has anti-inflammatory effects resulting in inhibition of cytokine release by macros and T cell activation.

Question 28

What is IL-3?

Answer 28

Produced by both TH1 and TH2 cells and CTLs, and serves as growth factor for hematopoietic progenitor cells in the bone marrow (similar effects to GMCSF)

Question 29

What is TNF-alpha?

Answer 29

Produced by both TH1 and TH2 and CTLs and serves as activation signal for macros and as activator or vascular endothelium.

Question 30

What is GMCSF?

Answer 30

Produced by both TH1 and TH2 cells and CTLs and serves as a growth factor for hematopoietic progenitor cells in bone marrow, resulting in increased production of macros and granulocytes

Question 31

What is TGF-beta?

Answer 31

Anti-inflammatory cytokine produced by Tregs (primarily). Most important function is to prevent activation of self-reactive T-cells

Question 32

What is IL-17?

Answer 32

Produced primarily by TH17 cells and serves as a signal for induction of neutrophil chemokines by endothelial cells.

Question 33

How does signaling through cytokine receptors work?

Answer 33

Heterodimers- IC domain of each monomer associated with Janus kinase proteins (JAKs)

When JAKs in close proximity, due to cytokine binding, they become enzymatically active and phosphorylate receptor

Once phosphorylated, they become ligand for transcriptions factors (STATS), which are then phosphorylated

Post-phosphorylation, STATS dimerize and move into nucleus where they initiate transcription of cytokine gene

Question 34

List the effector molecules of TH1.

Answer 34

CD40, IL-2, IL-3, IFN-gamma, TNF-alpha, LT, and GM-CSF

Question 35

List the effector molecules of TH2.

Answer 35

CD40, IL-3, IL-4, IL-5, IL-10, and TGF-beta

Question 36

List the effector molecules of Tregs.

Answer 36

TGF-beta and IL-10

Question 37

List the effector molecules of TH17.

Answer 37

IL-17 and IL-22