T-Cell Immunity (Immunology)

Front 1

Dendritic cells carrying antigens from the pathogen migrate to a secondary lymphoid site. What happens upon their arrival?

Back 1

DCs present epitopes to T cells, and T cells bearing TCRs that recognize epitopes become activated.

Front 2

What response provides initial protection against a pathogen AND promotes the maturation and migration of dendritic cells (carrying epitopes) to a nearby peripheral lymphoid site?

Back 2

Innate Response

Front 3

The maturation of dendritic cells at the site of the infection is induced by:

Back 3

interaction of TLR agonists with their receptors on immature dendritic cells.

Front 4

Naïve T cell activation occurs in peripheral lymphoid organs. Explain what is required to activate this T cell INITIALLY:

Back 4

Activation involves antigen-presentation by mature dendritic cells that originated at the site of infection and that present pathogen epitopes in the context of HLA class I and II.

Front 5

Following activation, what happens to the effector T cells?

Back 5

They leave the peripheral lymphoid site (origin) and traffick to the site of infxn.

Activated CD8+T cells target cells for destruction in which cytoplasmic localized pathogens (e.g. viruses) are present.

Activated CD4+ Th1 cells activate macrophages to kill vesicle-bound pathogens (e.g. Mycobacteria) and enhance the expression of certain IgG isotypes (e.g. IgG2a)

Activated CD4+ Th2 cells promote activation of B cells and the expression of certain IgG isotypes (IgG1 and IgE)

Front 6

TH1 cells

Back 6

Activate macrophages to kill vesicle-bound pathogens (e.g., Mycobacteria) and enhance the expression of certain IgG isotypes (e.g., IgG2a).

Front 7

TH2 Cells

Back 7

Promote the activation of B cells and the expression of certain IgG isotypes (IgG1 and IgE).

Front 8

Describe the cell-mediated immune respones for cytosolic pathogens:

Back 8

Viruses (e.g. vaccinia, influenza, rabies virus, and some intracellular bacteria (i.e. listeria)

CD8 cytotoxic T cell effector cells kills the virus-infected cells (cytosolic pathogens).

The CD8+cytotoxic T cell recognizes the viral peptides via peptide:MHCI complex and kills the cill.

This is an example of cell-mediated immunity.

Front 9

Describe the immune response for pathogens that are taken up into macrophages vesicles.

Back 9

(CD4) Th1 cells are involved. Microbes that persist in macrophage vesicles include (mycobacteria, listeria, pneumocystis carinii).

The (CD4) Th1 cells activate the infected macrophages and provide help to B cells for antibody production.They recognize the peptide:MHCII complex on infected macrophages.

This is an example of cell-mediated immunity.

Front 10

Describe the immune response for pathogens in the extracellular fluid.

Back 10

Clostridium tetani, staphylococcus aureus, strep pneumo, polio virus, pneumocystis carinii, and trichinella spiralis all reside in the extracellular fluid.

Th1 and Th2 cells are involved in the responses against these pathogens. They recognize peptide:MHCII complex on antigen-specific B cells. They work to activate specific B cells to make antibody.

Front 11

Explain how naive T cells traffic to and away from secondary lymphoid sites and how they become activated and exit the node:

Back 11

Naïve T cells enter node from arterial blood via high endothelial venules in a chemokine dependent migratory process. They enter parcortical areas where they contact mature dendritic cells. The T cells that do not encounter specific antigen reeive a survival signal through interaction with Self-Peptide:Self-MHC complex and IL-7 and return to circulation.

T cells they do encounter their specific antigen on mature dendritic cells lose ability to exit node, become activated, and proliferate/differentiate into effector T cells.

Days later, these antigen-specific T cells regain expression of receptors to exit node, leave efferent lymphatics, and enter circulation in great numbers.

Front 12

Describe the first interaction between dendritic cells and T cells.

Back 12

(You don't really have to read all of this to get the point)

The TCR portion of naïve T cell must be activated to activate the T cell via a conjugate with a dendritic w/appropriate peptide/HLA on cell surface. The affinity of TCR for peptide/HLA complex is really not that strong.

So the first interaction is that of an adhesion molecule. LFA-1 on T-cell binds ICAM on dendritic cells (macrophages, B cells, etc.).

T cells come into class proximity to APC with ICAM-1, and the contact there provides the initial glue to hold these cells together. If it binds apropriate HLA, that TCR will produce a signal which causes a conformational change in LFA-1, which increases the affinity of LFA-1 binding. This is a positive feedback system. The T cell can then increase the glue between these two cells, which keeps them together which allows for this T cell to become fully active.

Yes, T cells can become active by interacting with the MHC + peptide complex, but if the T cell LFA-1 binds the APC ICAM-1 molecule through a low-affinity interaction. When the T cell does bind to the MHC peptide complex, it signals a conformational change in LFA-1 on the T cell which increases affinity and prolongs cell-cell contact.

(LFA-1) or Lymphocyte function-associated antigen 1 is also found on all T-cells and (also on B-cells, macrophages and neutrophils and is involved in recruitment to the site of infection). It binds to ICAM-1 on antigen-presenting cells and functions as an adhesion molecule.

It is the first to bind T-cells to antigen-presenting cells and initially binds weakly. A signal from the T-cell receptor changes the conformation and prolongs the cell contact, allowing the T-cell to activate/proliferate. LFA-1 is part of the family of leukocyte integrins which are recognized by their common β-chains (CD18). LFA-1 also has a distinct α-chain (CD11a).

Front 13

Describe the steps necessary for activation of naive CD4+ T Cells.

Back 13

1. The T cell receptor must recognize the class II HLA-bound epitope.

2. CD4 on the T cell MUST associate w/ the class II HLA on the antigen presenting cell.

3. CD80/86 on the dendritic cell must interact with CD28 on the T cell

Front 14

Activation requirements for CD8+ T Cells

Back 14

1. Initial interaction with dendritic cell via adhesion molecules.
2. Recognition of epitope in the context of class I HLA.
CD8 association with class I molecule
3. CD28 on T association with CD80/86 on DC (same as CD4+ T cells)

Front 15

What is the major advantage of the requirement for the CD80/86 – CD28 interaction in the activation of naïve T cells?

Back 15

Prevention of clonal amplification of T cells bearing TCRs that recognize self peptides.
These cells are present because not all self antigens are present in the thymus.

Front 16

The requirement for for one cell to deliver both the antigen-specific signal and the co-stimulatory signal is crucial in preventing immune responses to self antigens. How does this process work?

Back 16

The requirement for one cell to deliver both the antigen-specific signal and the co-stimulatory signal is crucial in preventing immune responses to self antigens. (See p. 348 Janeway) In one case, a T cell recognizes a viral peptide on the surface of a DC and is activated to proliferate and differentiate into an effector T cell capable of eliminating any virus-infected cell.

In the contrasting case to this, naïve T cells recognizing self- antigen on epithelial cells that cannot provide co-stimulation become anergic, so when a T cell recognizes a self antigen expressed by an uninfected epithelial cell (lower panels), it does not become activated.

This T cell does not differentiate into an effector cell and cannot even be activated by a subsequent encounter with a dendritic cell bearing the same antigen.

Front 17

In regards to T cell activation, what signal dampens the proliferative phase of the response by reducing the sensitivity of the T cell to stimulation by the APC and limits the production of the T cell growth factor, Interleukin-2 (IL-2)?

Back 17

CTLA-4 expressed on the T cell surface.

Remember that CD28 on the T cell binds B7 (CD80/86) on the APC. This provides the costimulatory signal during activation of naive T cells and induces expression of CTLA-4.

CTLA-4 binds B7 at a > affinity than CD28, and provides inhibitory signals to activated T cells.

Front 18

When a CD8+ T-cell becomes an effector cell, does it require the expression of CD80/86 on cell that it targets for apoptosis?

Back 18

No.

Front 19

When a CD4+ TH-1 cell becomes an effector cell, does it require the expression of CD80/86 on the macrophage in order to activate the macrophage?

Back 19

No.

Front 20

When a CD4+ Th2 cell becomes an effector cell, does it require the expression of CD80/86 on the B cell in order to activate the B cell?

Back 20

No.

Front 21

Antigen-induced activation of a T cell following presentation of an epitope by a dendritic cell results in the production of key T cell surface receptors including:

Back 21

CD40 ligand, high affinity IL-2 receptors, and cytokines (IL-2, IL-4, G-interferon, TNFa and b)

Front 22

The expression of which membrane component is a key step in the "arming" of CD4+ T cells?

Back 22

The induction of CD40 ligand on CD4+ T cells. CD40 ligand on CD4+ T cells interacts with CD40 on Bcells and Macrophages. CD40 ligand induction is a critical step in the CD4+ Th1 cell activation of macrophages and the CD4+ Th2 activation of B cells.

Front 23

CD4+ Th 1 cells activate

Back 23

Macrophages

Front 24

CD+ Th 2 cells activate

Back 24

B cells only

Front 25

A patient comes to your office whose activated T cells do not express CD40 ligand. He is 5 years old and has a history of several episodes of otitis media, penumonia from an infection with Pneumocystis carinii, and streptococcal infections of the skin.

Analysis of serum immunoglobulins revealed an IgG level of 25 mg/dl (normal 600-1500), no IgA (normal 75-150 mg/dl), and IgM of 210 mg/dl (normal 75-150 mg/dl).

Explain the consequences of this patient's defect?

Back 25

Without CD40 ligand expression, Th2 cells cannot activate B cells to become antibody-producing plasma cells. Germinal centers are sites of proliferation for B cells that have been activated by armed Th2 cells.

In this patient, germinal centers may not be seen, and this patient has "X-linked-hyper-IgM syndrome" which are immunoglobulins are surface of immature B cells.

Front 26

What is the underlying defect in patients with X-linked-hyper IgM syndrome?

How will this affect the patient?

Back 26

Absence of CD40 Ligand expression on T cells.

Since CD40 ligand expression is also important in the interaction of Th1 cells with macrophages, the activation of macrophages and thus the intracellular killing of pathogens is markedly reduced.

Thus Dennis Fawcett had a history of infections that included pneumonia from an infection with Pneumocystis carinii, a pathogen that is taken up and destroyed only by activated macrophages.

Serum immunoglobulins are also affected because of the fact that CD40 ligand is not present on surface of Th2 cells.

Thus lack of CD40ligand on Th1 and Th2 impairs the functional operation of these cells as well.

Front 27

Summarize the key cell<-->cell Interactions in the Arming of a T cell by an Antigen-presenting Dendritic Cell:

Back 27

1. Adhesion molecules (e.g., LFA-1/ICAM-1) increase binding affinity and hold the cells together for the necessary time. (The T cell needs time to LAF "laugh/smile" at the "Macrophage" MACintosh Camera).

2. TCR (on T cell):epitope/HLA I or II (on APC) is the required signal for activation

3. CD28 (on T cell): CD80/86 (on APC) provides the necessary costimulatory signal

4. Induction of CD40 ligand on CD4+ T cells and interaction of CD40 ligand:CD40 on Dendritic cell. The CD40 on APC binds CD40L and causes cytokine release in T cell as well as the next step.

5. Induction of CTLA-4 on T cells results in decreased sensitivity to dendritic cell and decreased production of IL-2.

Front 28

CD40 is located on the

Back 28

dendritic cell.

Front 29

Which processes are upregulated by TLR agonists and type I interferons.

Back 29

The following are upregulated by TLR agonists and are especially important for macrophages and B cells.

HLA I or II on APC
CD80/86 on APC
CD40 on Dendritic Cell

Front 30

Describe dendritic cell:

a) antigen uptake
b) MHC expression
c) co-stimulator delivery
d) types of antigen presented
and e) location

Back 30

a) antigens are taken up by +++ macropinocytosis and phagocytosis by tissue dendritic cells. Viral infection.

b) MHC expression is low on tissue dendritic cells but high on dendritic cells in lymphoid tissue.

c) Co-stimulator delivery constitutive by mature, nonphagocytic lymphoid dendritic cells

d) Presents peptides , viral antigens and allergens

e) located ubiquitously throughout the body

Front 31

Describe macrophage:

a) antigen uptake
b) MHC expression
c) co-stimulator delivery
d) types of antigen presented
and e) location

Back 31

a) antigens taken up by phagocytosis ONLY +++
b) MHC expression is inducible by bacteria and cytokines - to +++

c) Costimulator delivery is inducible - to +++

d) Antigen presented ? particulate antigens, intracellular and extracellular pathogens.

e) location? Lymphoid tissue, connective tissue, and body cavities (location a bit more specialized than dendritic cells).

Front 32

B cells:

a) antigen uptake
b) MHC expression
c) co-stimulator delivery
d) types of antigen presented
and e) location

Back 32

a) antigen up take? Antigen-specific receptors aid uptake (Ig) ++++

b) MHC expression constituive increases on activation +++ to ++++

c) costimulator delivery is inducible - to +++

d) Antigen presented? Soluble antigens, toxins, and viruses

e) Located in lymphoid tissue and peripheral blood as it is disseminated.

Front 33

The production of IL-2 following antigen-presentation is a key step because:

Back 33

IL-2 (T cell growth factor) promotes the proliferation of T cells bearing high affinity IL-2 receptors.

Front 34

Which T cells express high affinity IL-2 receptors?

Back 34

Only those that have interacted with a dendritic cell bearing an epitope bound to HLA that is recognized by the T cell. This allows for clonal expansion of T cells that recognize pathogen epitopes.

Front 35

Summarize the maturation of Naive CD4+ T cells

Back 35

Naive T cells interacts with APCs via cell adhesion and expresses high affinity IL-2 receptor and releases IL-2 upon activation leading to entry into the cell cycle and proliferation.

The cells proliferate and begin immature effector cells (Tho) which can then diverge to become either Th1 cells (which activate macrophages) and Th2 cells (which activate B cells)

Front 36

Cytokine profile of Th1 Cells:

Back 36

1. IL-2: (T cell growth factor) which induces T cell proliferation

2. Interferon-gamma and TNF-alpha: Activates macrophages; leads to increased HLA expression

Front 37

Cytokine profile of Th2 Cells:

Back 37

1. IL-4: B cell activation; class switching to IgG1 and IgE

2. IL-5: B cell activation; eosinophil growth and differentiation

3. IL-6: B cell activation; enhances Th2 cell development

4. IL-10: Inhibits the generation of Th1 cells

5. IL-13: B cell activation; class switching to IgG1 and IgE

Front 38

IL-4 Function

Back 38

Released by Th2 cells.

B cell activation; class switching to IgG1 and IgE

Front 39

IL-5 Functoin

Back 39

Released by Th2 cells.

B cell activation; eiosinophil growth and differentiation

Front 40

IL-6 Function

Back 40

Released by Th2 cells.

B cell activation; enhances Th2 cell development.

Front 41

IL-10 Function

Back 41

Released by Th2 cells.

Inhibits the generation of Th1 cells.

Front 42

IL-13 Function

Back 42

Released by Th2 cells.

Class switching to IgG1 and IgE

Front 43

IL-2 Function

Back 43

Released by Th1 cells.

Leads to T cell proliferation

Front 44

Interferon-gamma function and TNF-Alpha function (in relation to T cells)

Back 44

Macrophage activation; increased HLA expression

Front 45

What are the 3 key steps of T cell activation?

Back 45

1. Recognition of an epitope.

2. Amplification via proliferation in response to IL-2.

3. Expression of chemokine receptors and adhesion molecules that guide T cells to site of infection.

Front 46

Do effector cells require co-stimulation to respond to their targes?

Back 46

No. They begin as naive T cells, which DOES require both a TCR and CD28/B7 binding to become active. An IL-2 secretion and self-IL-2-response induces differentiation of the T cells to the actual effector cells.

Effector cells can then kill a cell or activate a macrophage or B cell w/o costimulation

Front 47

CD25

Back 47

It is expressed on activated T cells, B cells and monocytes. It basically is the IL-2 receptor alpha chain that affords the T cell with high affinity to IL-2

Front 48

The differentiation of Th1 cells from Th0 cells.

Back 48

Is enhanced by IL-12 and IFN-gamma

Front 49

The differentiation of Th2 from Th0 cells.

Back 49

Is enhanced by IL-4