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Flashcards in Cellular Immunity week 2 Deck (19)
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How do naive T cells (from the thymus) enter lymphoid tissue? What vessels do they enter through? Where do they go once in lymphoid tissue? Explain the receptors involved in this process.

Once in the lymph node, what cells to T-cells interact with?

Initially the naïve T-cells (from the thymus) enter lymphoid tissue through high endothelial venules and travel into the T-cell rich zone where they will encounter dendritic cells (DCs)/macrophages presenting peptide antigen within the binding groove of MHC molecules.

How T-cells get into lymph tisssue to interact with macrophages and DCs: Once in the lymph tissue, binding of L-selectin on naive T-cells with GlyCAM-1 and CD34 on cells in the lymph node allow a rolling interaction. Chemokines expressed in the extracellular matrix of the lymph node activates LFA-1 on the surface of T-cells and promotes LFA-1 binding to ICAM-1. This interaction leads to diapedesis of the T-cell into the lymph node. Please see slide 4 of PP for pictures illustrating this process.



How do T-cells initially bind DCs in the lymh node? Through what receptors is this interation strengthened? What triggers the increase in affinity of binding btwn these cells? What is the purpose of this?

T-cells initially bind DCs through low affinity binding btwn LFA-1 receptor on T-cells and ICAM-1 receptor on DCs. Engagment of the TCR with MHC triggers LFA-1 to change conformation and bind to ICAM-1 with higher affinity. This prolongs cell to cell contact.

The interaction between TCR and peptide/MHC complex is usually weak so increased adhesion receptor and ligand interaction will aid in facilitating a strong signal from the TCR.


Interaction between what molecules on T-cells and antigen presenting cells (APCs) is critical for inducing differentiation of naive T-cells? What happens if this does not occur?

What is the other critical receptor ligand pair involved in provoking naive T-cell differentiation?

Another important receptor-ligand pair is CD28 (on T-cells) and B7.1(CD80)/B7.2(CD86) (on antigen presenting cells). This second signal is vital to inducing differentiation of naïve T-cell into an effector cell. Without it the T-cell will become anergic (see lecture on Immune Regulation and Tolerance).

One other critical receptor ligand pair involved in provoking naïve cell differentiation to effector cells is CD4 to MHCII or CD8 to MHCI interaction.

Triggering all three receptors (TCR, CD28 and CD4/CD8) will lead to signal that leads to proliferation and differentiation of the naïve T-cell.


What are the two key events following triggering of the 3 activation receptors (TCR, CD28, and CD4/CD8)? What does this do for the T-cell?


Two key events following triggering of the three activation receptors are the induction of IL-2 receptor and production of IL-2.

Interaction of IL-2 with its receptor leads to signals that induce proliferation of the antigen specific T-cell.

The naïve T-cell differentiates into effector T-cell.


Once a T-cell becomes an effector cell, what signaling molecule is no longer needed? What signaling molecules are necessary for effector cells to respond to peptide antigen presented by MHC molecules?

Once a T-cell becomes an effector cell it no longer needs CD28. Engagement of TCR and CD4 or CD8 is all that is necessary for effector cells to respond to the peptide antigen presented by MHC molecule.


Most T-cells become effector cells. What is the other option for these activated T-cells?

T-cells may also become memory cells.


What type of lymphcyte repsonds to extracellular microbes? How do these cells eleminate microbes?

What type of lymphocyte responds to intracellular microbes? (just list)

Extracellular microbe: need antibodies so B cells respond (humoral immunity). B-cells differentiate into plasma cells and eliminate microbes through various mechaisms including neutralization, prevention of microbes from binding to surface, oposonization, activation of complement, etc.

Intracellular microbes: need cell mediated immunity: T-cells


How do pathogens get itnto cells?

T-cells respond to intracellular microbes. What is the difference btwn the type of intracellular microbes that CD4+ helper T-cells and CD8+ cytotoxic T-lymhphocytes (CTL) respond to?

Why do different cells respond to intracellular microbes? (What triggers the response of one T-cell type over the other?)

Intracellular pathogens are brought into a cell either by phagocytosis or by infection.

  • Phagocytosed pathogens reside and expand within vesicles of the infected cell.
  • Pathogens brought into the cell by infection reside and propagate within the cytoplasm.
  • In rare instances pathogens may enter the phagocyte after phagocytosis but escape from the vesicle into the cytoplasm (e.g. Listeria monocytogenes) where they reside and propagate.

Antigens from pathogens residing in vesicles (e.g., intracellular bacteria) trigger CD4+ T-cells or T-helper (TH) cells. T-helper cells are activated rather than CD8+ T-cells because MHC class II molecules present antigens from pathogens residing in vesicles.

Antigens from pathogens residing in the cytoplasm (e.g., virus) trigger CD8+ T-cells or cytotoxic T-lymphocytes (CTL). Viral antigens that are present in the cytoplasm are presented by MHC class I molecules.


What molecule is expressed on CD4+ T-cells after activation of the TCR through binding of MHC class II on macrophages? What does this molecule bind to on macrophages?

Engagement of the TCR leads to production of what cytokine?

What are the effects of these two processes?

When T-cell antigen receptor (TCR) on CD4+ T-helper binds to the peptide antigen in the context of MHC class II molecule on the macrophage the CD4+ T-cell expresses CD40 ligand (CD40L). CD40L binds to CD40 receptors on the macrophages. Engagement of TCR also leads to interferon-gamma (IFN-γ) secretion. Triggering CD40 on macrophages by CD40L as well as IFN- γ binding to its receptor on macrophages leads to macrophage activation.

At the level of effector function, B7.1 and B7.2 are not needed in order TH cells to respond to antigen in the context of MHC class II molecules. Only during priming of naïve CD4+ T-cells does B7.1 and B7.2 become necessary.


How do activated macrophages enhance antigen presentation to T-helper cells?

Activated macrophages do the following to enhance antigen presentation to T-helper cells:

a) Increase surface expression of MHC class II molecules

b) Increased surface expression of costimulatory (B7.1 & B7.2) molecules

c) Secrete IL-12, pro-inflammatory cytokines (IL-1, TNF-alpha and IL-6) and chemokines.

These three events (a-c) lead to increased recruitment of macrophages and convert antigen specific naïve T-cells into effector T-helper cells. In other words, enhancement in antigen presenting properties of macrophages amplify immune response against the intracellular pathogen.


What do activated macrophages do to enhance the destruction of intracellular pathogens?

Activated macrophages do the following to enhance destruction of intracellular pathogen:

a) Induces production of reactive oxidative products

b) Increases production of lysozymes

c) Increases reactive oxygen species (ROS) production

d) Induces nitric oxide (NO) production by increasing expression of inducible NO synthase (iNOS).

i. NOS converts arginine together with NADPH and O2 to citrulline and NO.

ii. NO together with reactive oxygen species leads to the death of almost all microorganisms.

 e) Increases inflammatory cytokine production by macrophages.



Explain the steps involved in CTL function. State what MHC molecule binds to TCRs on CTLs and the result of this binding.

Cell-mediated immunity mediated by cytotoxic T-lymphocytes:

1. T-cell antigen receptors (TCR) on CTLs recognize peptide from the intracellular pathogen, which replicate in the cytoplasm and therefore are presented by MHC class I molecules. The CD8 molecule also engages a MHC-I molecule on the infected cell.

2. Steps involved in CTL function

a. A tight junction occurs between ICAM-1 on infected cell and LFA-1 on CTL called an “immune synapse (IS)”. IS allows for localized release of lytic granules. This only occurs after engagement of TCR with peptide presented by MHC class I molecule. In this way only the infected cell that triggers the TCR is killed. IS prevents neighboring uninfected cells from being killed by the CTL.

b. Triggering TCR both increases adhesion to the infected target cell and induces the CTL to release content of lytic granules containing perforin and granzymes onto the infected cell surface.

c. The infected cell following CTL’s degranulation internalizes perforin and granzymes. Perforin and granzymes lead to the destruction of the infected cells through apoptosis. Perforin perforates the cell membrane to allow for entry of granzymes into the cell. Granzymes trigger apoptosis.

d. Upon completing the lethal blow, the CTL detaches and continues to find the next infected cell where again it release the lytic cargo onto the infected cell surface. In this way CTL are focused serial killers.

3. At the level of effector function, B7.1 and B7.2 are not needed in order for CTLs to respond to antigen in the context of MHC class I molecules. Only during priming of naïve CD8+ T-cells does B7.1 and B7.2 become necessary.

4. In rare instances pathogens (e.g., Listeria) escape vesicles after entry into macrophages and enter into the cytoplasm. These organisms are eliminated by CD8+ T-cells through destruction of the infected macrophage.

Note: CD40 and CD40 ligand are NOT involved in CD8+ T-cell responses.


In what circumstance to CD4+ and CD8+ T-cells act on the same cell? Why does this occur?

When macrophages ingest pathogens, the pathogens are contained within vesicles. If some escape, they are now in the cytoplasm of the cell. In this instance, CD4+ T-cells bind to and activate the macrophage through MHC II receptors. IFN-gamma is released and triggers degradation of pathogen in the phagylosomes. After this occurs, CD8+ T-cells are engaged to trigger apoptosis of the infected cell. These two cells work together to ensure the pathogen is completely destroyed.


Are NK cells part of innate or adaptive immunity? What CD molecule do NK cells express that distinguishes them from T-cells?

What is contained within the cytoplams of NK cells? What cytokines may NK cells produce? What cells do these cytokines act on?

1. Natural killer (NK) cells mediate innate cellular immune responses. NK cells express CD56 a marker that distinguishes them from T-cells. THEY DO NOT EXPRESS TCR/CD3 OR Ig ON THEIR SURFACE.

2. These cells contain large granules within their cytoplasm that contain perforin and granzymes (similar to what is found within CD8+ T-cells). Because the numerous granules make them dense these cells are called large granular lymphocytes.

3. NK cells are cytolytic in nature but may also respond to cytokines from macrophages (IL-12) and begin to produce cytokines such as interferon-gamma. Thus, functionally they are like T-helper cells and cytotoxic T-lymphocytes.


What ligands trigger activation of NK receptors? What NK receptor is engaged by these ligands?

NK cells kill infected cells through recognition of a variety of ligands by activation receptors.

a. The activation receptors are germline encoded.

b. Activation receptors are associated with adaptor molecules, which are

c. Ligands for activation receptors can be: involved in down stream signal transduction.

Ligands to the NK cell activation receptor, NKG2D, are Danger-Associated Molecular Patterns (DAMPs).

NKG2D ligands are expressed on surface of cells that are stressed. For example, radiation can damage DNA in cells. The cell will attempt to repair DNA damage but thorough this can have mutations and lead to cancer. The cells expresses DAMPs. NK cell binds to these DAMPs through NKG2D and triggers apoptosis of the cell.

Ligands for activation receptors can be:

i. Pathogen or tumor-derived molecules (e.g., BAT3 or B7-H6 trigger NKp30)

ii. Induced by cellular/genotoxic stress (e.g., HCMV UL-16 binding protein triggers NKG2D)

iii. Constitutively expressed (e.g., CD48 triggers 2B4)

iv. Peptides presented by MHC class-I molecules (HLA-A, -B and -C, leader peptides presented by HLA-E trigger NKG2C/CD94)



Why do NK cells express inhibitory receptors? What do these inhibitory receptors bind to? What is the result?

Inhibitory receptors

a. NK cells possess inhibitory receptors in order to to prevent destruction of normal cells by NK cells. This is important since some of the activation ligands are constitutively expressed on cells.

b. Inhibitory receptors primarily recognize MHC class I molecules.

Since almost every cell in the body express MHC class I molecules, then it is likely that NK cells will not respond to normal cells because they possess inhibitory receptors that recognize MHC class I molecules on their surface.


Which HLA class I molecule presents leader seqeunces of other HLA class I molecules to signal the cell is normal to NK cells? What occurs in the absence of this molecule?



Which is the typical result of NK cells binding to cell surface molecules: inhibition or activation?

How do many pathogens and tumors avoid recognition by CTLs? How does this make them vulnerable to NK cells?

Typically inhibition overrides activation. Although if activation signals are greater than inhibition signals NK cell responds to the target cell.

Many pathogens and tumors avoid recognition by CTLs by down modulating MHC class I molecules. However, this make the pathogen infected cells or tumor cell vulnerable to attack by NK cells since they lack MHC class I molecules and would not be able to trigger the inhibitory receptor on the NK cells.


Pathogen infected target cells or tumor cells bound by Ab are targets for NK cell destruction through what mechanism? Describe this process and the receptors involved. What Ig is this mediated through? (IgM, IgE, etc.)

Antibody dependent cell-mediated cytotoxicity (ADCC)

a. Pathogen infected target cells or tumor cells bound by antibody are targets for NK cell destruction by a mechanism know as antibody-dependent cell-
mediated cytotoxicity (ADCC).

b. ADCC occurs when Fc gamma receptor type III (FcRγIII or CD16) on the NK cells binds to the Fc portion of a IgG molecule.

c. FcRγIII bound by antibody triggers NK cells to release the lytic content of their granules onto the pathogen-infected cell surface and in turn kill the infected cell.

Note: CD16 is not as sensitive to inhibitory signals as the NKG2D receptor. The Ab signal is so strong that it overrides inactivation.