(10) T Cell Maturation & Activation

Do T cells respond mostly to intracellular or extracellular microbes?

intracellular

(B cells = extracellular)

What must happen to an antigen before a T cell responds to it?

phagocytosis

(microbe may survive in phagolysosomes or escape into cytoplasm)

For many antigens, they must be phagocytosed before a T cell responds. The microbe may survive in phagolysosomes or escape into the cytoplasm. What is an example of a microbe that does NOT have to undergo phagocytosis to enter the cell?

virus

(just binds to receptors and enters cytoplasm to cause infection)

Where are T cells made?

bone marrow

Where do T cells mature?

thymus

refers to a T cell that has CD3 but no CD4 or CD8

pro T cell

("double negative")

refers to a T cell that has CD3 and expresses the beta chain of the TCR

pre T cell

refers to a T cell that has CD3 and also both CD4 and CD8, as well as the TCR

immature T cell

("double positive")

refers to a T cell that has CD3 and either CD4 or CD8, as well as the TCR

mature T cell

maturation process in which T cells must weakly recognize an MHC molecule in order to survive

If they weakly recognize an MHC class II molecule on an APC, then it becomes a CD4+ helper T cell.

If they weakly recognize an MHC class I molecule on an APC, then it becomes a CD8+ cytotoxic T cell.

positive selection

If an immature T cell weakly binds to the peptide presented by the MHC II molecule on the APC, then what kind of T cell does it become?

CD4+ helper

If an immature T cell weakly binds to the peptide presented by the MHC I molecule on the APC, then what kind of T cell does it become?

CD8+ cytotoxic

We have a subset of APCs that can present antigens to double positive immature T cells. That triggers either weak binding of the MHC II peptide on the APCs to CD4 or weak binding of MHC I peptide to CD8. In either case, whichever MHC's peptide is weakly recognized, that's what kind of T cell we get. What happens to these now mature cells next?

migrate to peripheral lymphoid organs

We have a subset of APCs that can present antigens to double positive immature T cells. That triggers either ____ binding of the MHC II peptide on the APCs to CD4 or ____ binding of MHC I peptide to CD8. In either case, whichever MHC's peptide is ____ly recognized, that's what kind of T cell we get.

weak

What happens if positive selection fails? (i.e. immature T cell recognizes neither MHC's peptide)

apoptosis

What happens if immature T cells strongly recognize one of the MHC molecules on the APC?

apoptosis

(they are self peptides, so we don't want to make T cells that are primed to attack our own tissue)

process in which T cells that strongly recognize an MHC molecule undergo apoptosis

negative selection

True or false: T cells require APCs to recognize an antigen and be activated.

true

Once the TCR interacts with an MHC on an APC, it is activated. What smaller molecules enhance this activation and lead to clonal expansion?

cytokines

refers to the rapid multiplication of lymphocyte cell clones after activation by an antigen; all of these "clones" are unique to the antigen that activated the original lymphocyte

clonal expansion

Once lymphocytes have proliferated in clonal expansion, they undergo differentiation. They may become which two types of cells?

effector, memory

Where does T cell antigen recognition occur?

peripheral lymphoid organs

Where does activation of T cells occur?

peripheral lymphoid organs

Where does clonal expansion of T cells occur?

peripheral lymphoid organs

Where does differentiation of T cells occur?

peripheral lymphoid organs

Where do T cells carry out their effector functions?

peripheral tissues

Where are the CD4+ T-cells activated? (SELECT 2)

A. lymph node

B. thymus

C. bone marrow

D. spleen

E. blood

A, D

How does a TCR recognize an antigen? (Hint: Where is the antigen?)

antigen peptide is within an MHC

Which class of MHC does CD4 on a helper T cell bind to?

class II

Which class of MHC does CD8 on a cytotoxic T cell bind to?

class I

TCR signaling begins with what happening to the zeta-zeta chains associated with CD3?

phosphorylation

What part(s) of the TCR complex actually transduces the signal once the MHC antigen peptide binds to the TCR?

CD3 and zeta-zeta chains

What part of the TCR complex is phosphorylated to initiate signaling?

zeta-zeta chains

True or false: Two or more TCRs and co-receptors (CD4 & CD8) need to be engaged for a period of time to initiate a response.

true

(just in case we get a "rogue" single interaction - we want to make sure it's truly the antigen that needs to be attacked before we get a full blown response)

Helper T cell activation requires what 2 signals?

MHC/peptide antigen binding to TCR and CD4, costimulatory molecule on APC binding to specific receptors on T cell

Helper T cell activation requires 2 signals:

1. MHC/peptide antigen binding to what two molecules?

2. What on the APC binding to what on the T cell?

TCR and CD4, B7 to CD28

costimulatory molecule on APCs that binds to CD28 on T cells to activate them

B7

(specifically B7-1, which is excitatory, or B7-2, which is inhibitory)

receptor on T cells that interacts with B7 co-stimulatory molecules on APCs to promote T-cell activation

CD28

When the MHC/peptide antigen complex binds to the TCR and CD4, and B7 binds to CD28, this triggers the release of cytokines, which play a role in what process that occurs next?

proliferation

Activated APCs (in CD4+ T cell activation) release which cytokines?

IL-12

When activated APCs release IL-12, this stimulates the activated T cell to release what other cytokine and also express a receptor for that particular cytokine?

IL-2

(so T cells release IL-2, comes back to bind to the T cell that released it, triggering proliferation)

Once IL-12 from activated APCs stimulates T cells to release IL-2 and express IL-2 receptors, this results in what two processes occurring next?

clonal expansion, differentiation

refers to an unresponsive T cell resulting from no co-stimulation (T cell engages MHC but no B7 involved)

anergy

(T cell may also undergo apoptosis)

True or false: All APCs, activated and unactivated, express the B7 costimulatory molecule.

false

(only activated APCs, therefore only naive T cells in direct contact with APC that contains microbial antigen will be activated)

Cytotoxic T cell activation requires what 2 signals?

MHC/peptide antigen binding to TCR and CD8, costimulatory molecule on APC binding to specific receptors on T cell

Cytotoxic T cell activation requires 2 signals:

1. MHC/peptide antigen binding to what two molecules?

2. What on the APC binding to what on the T cell?

TCR and CD8, B7 to CD28

CD8+ T cells are more specific for virally infected cells. That cell can now start expressing things on its surface that will lead to phagocytosis. The APC phagocytoses the entire infected cell, and that infected cell now lives in a phagolysosome within the APC. What cells do the APCs present to now: CD8+ or CD4+?

both

(cross presentation)

One APC can activate both a CD8+ T cell and CD4+ T cell. When it interacts with the CD8+ T cell, we get the MHC class I/TCR complex and B7/CD28 complex to activate it.

However, when it activates the CD4+ T cell, those helper T cells secrete cytokines that induce what with the CD8+ T cells?

proliferation

A different mechanism for activating a CD8+ T cell is when the APC itself is infected. When this happens, it processes those antigens via the MHC class I pathway. When this happens, infected APCs express what co-stimulator molecules, which trigger T cells to secrete self-activating cytokines?

B7

Vitamin D has been shown to play a role in T cell activation and improving the immune response. Basically, vitamin D gets into the cell and binds its receptor. That vitamin D-receptor complex upregulates what enzyme, which enhances T cell activation?

phospholipase C gamma 1

How long after initial exposure does it take to get differentiated effector cells?

3-4 days

Activation, clonal expansion, and differentiation have occurred, and now T cells have effector functions. What are the main effector functions of CD4+ T cells? (2)

macrophage/B cell activation

ligand expressed by effector CD4+ T cells that plays a role in macrophage activation and B cell activation

CD40L

CD40 ligand is expressed by effector CD4+ T cells and binds to CD40 on what other kind(s) of cells?

macrophages, B cells

When binding to macrophages via the CD40 ligand, CD4+ T cells are triggered to secrete what cytokine(s) that bind to macrophages to trigger them to destroy phagocytosed microbes?

IFN-gamma

When binding to B cells via the CD40 ligand, CD4+ T cells are triggered to secrete what cytokine(s) that bind to B cells (that serve as APCs) and result in antibody secretion and Ig class switching?

IFN-gamma, IL-4

What do CD4+ T cells trigger in macrophages upon secretion of IFN-gamma?

phagocytosis and killing of microbes

What do CD4+ T cells trigger in B cells upon secretion of IFN-gamma and IL-4?

antibody secretion and Ig class switching

predominant subtype of CD4+ helper T cells

Th1 cells

CD4+ T cells that have differentiated into this type due to macrophages and dendritic cells secreting IL-12 in response to bacterial or viral infections

Th1 cells

Naive CD4+ T cells may differentiate into Th1 cells when macrophages and dendritic cells release what in response to infections?

IL-12

When Th1 cells secrete IFN-gamma, what does this cause in macrophages?

activation

When Th1 cells secrete IFN-gamma, what does this cause in B cells?

IgG production

(involved in phagocytosis via Fc receptors)

Once Th1 cells are formed due to release of IL-12 from macrophages and dendritic cells, what do they secrete?

IFN-gamma

(causing macrophage activation and IgG production)

CD4+ T cells that have differentiated into this type due to no production of IL-12 by the APC and therefore the T cell itself secreting IL-4

Th2 cells

Naive CD4+ T cells may differentiate into Th2 cells when there is a lack of what cytokine not produced by the APCs?

IL-12

Naive CD4+ T cells may differentiate into Th2 cells when there is a lack of IL-12 and therefore the T cell itself secretes what other cytokine to induce differentiation?

IL-4

When are Th2 cells produced? (i.e. Infections with what?)

large parasites (too big to be phagocytosed), other microbes that fail to stimulate IL-12 secretion

Once Th2 cells are secreted, what two things do they secrete?

IL-4, IL-5

When Th2 cells secrete IL-4, what immunoglobulin is produced?

IgE

(for mostly parasitic infections)

When Th2 cells secrete IL-4, what happens in the GI tract?

peristalsis, production of intestinal mucus

(prevents parasites from binding to GI epithelium)

When Th2 cells secrete IL-4, what cells are activated?

macrophages

When Th2 cells secrete IL-5, what cells are activated?

eosinophils

Are IgE production, macrophage activation, and GI effects stimulated by IL-4 or IL-5 secretion by Th2 cells?

IL-4

Are eosinophils stimulated by IL-4 or IL-5 secretion by Th2 cells?

IL-5

3 cytokines released by Th2 cells to counteract IFN-gamma (released by Th1 cells) and inhibit standard macrophage activation and Th1 mediated immunity

IL-4, IL-10, IL-13

Th2 cells inhibit the activation of inflammatory macrophages. Instead, the macrophages they activate (mostly via IL-4) are involved in what?

tissue fibrosis and repair

(after inflammation)

CD4+ T cells activated (via APCs) in response to certain bacteria and fungi that secrete IL-17 and IL-22 to help strengthen the inflammatory response

Th17 cells

What four cytokines released by macrophages induce the differentiation of Th17 CD4+ cells?

IL-1, IL-6, IL-23, TGF-B

2 cytokines released by Th17 that play a role in strengthening the inflammatory response

IL-17, IL-22

True or false: Effector CD8+ cytotoxic T cells do not require costimulation or help from CD4+ T cells for activation.

true

Cytotoxic CD8+ T cells kill their target cells by releasing granules filled with what enzymes?

**these enter the target cell via perforin pores in the endocytic vesicles and activate caspases, resulting in apoptosis

granzymes

Granzymes are released by CD8+ T cells and enter their target cells via what process?

receptor mediated endocytosis

Granzymes are released by CD8+ T cells and enter their target cells via receptor mediated endocytosis. The granzymes enter the target cell cytoplasm via perforin pores in the endocytic vesicles and then activate what type of enzyme to induce apoptosis?

caspase

Which of the following cytokines stimulates the differentiation of a CD4+ T-cell into a Th1 cell?

A. IL-4

B. IL-12

C. IFN-gamma

D. IL-2

E. IL-10

B

Which of the following is NOT involved in CD8+ T-Cell activation?

A. MHC class I

B. B7

C. CD40L

D. cytokines

C

How have mycobacteria developed resistance to cell-mediated immunity?

inhibit phagolysosome fusion

(so enzymes from lysosomes can't get in and break down the mycobateria)

How have certain viruses developed resistance to cell-mediated immunity in regards to APCs?

inhibit MHC class I expression

(specifically, CMV/EBV inhibit proteosomal activity, HSV inhibits transport of peptides into the ER, and CMV removes class I MHC from ER)

How have certain viruses developed resistance to cell-mediated immunity in regards to cytokines? (2)

produce inhibitory cytokines or soluble cytokine receptors

An example of viral resistance to cell-mediated immunity is Epstein-Barr virus stimulating the secretion of what inhibitory cytokine that inhibits macrophage activation?

IL-10

An example of viral resistance to cell-mediated immunity is the pox virus producing ____ ____ ____ that take up all of the ("quench") cytokine before the target cells can get to it.

soluble cytokine receptors

____ T cells release perforin.

A. Cytotoxic

B. Helper

C. Suppressor

D. Regulatory

E. Inhibitory

A

(both cytotoxic T cells and NK cells release perforin)

Which of the following would NOT present a foreign antigen within MHC-II proteins?

A. macrophage

B. liver cell

C. dendritic cell

D. B cell

E. Neither B nor D

B

Indicate which type of cell is being described by these statements:

1. Enhance the development of antigen-stimulated B cells into antibody-secreting cells

2. Secrete interleukin 2

3. Recognize class II MHC glycoproteins

A. cytotoxic T cells

B. helper T cells

C. suppressor T cells

D. macrophage

B