1. Eliminating cells via antibody that are modified by intracellular pathogens or by transformations

    - cells that are innapropriately formed express that  

      something is wrong with them

2. Cells express different cell-surface antigens.

     - when evaded by pathogens

1. What is the function of cell-mediated cytotoxic immunity?

2. What types of cells are involved?

3. What are the activities of the cells dependent on?

1. Fn: Detection and elimination of cells that harbor intracellular pathogens by recognizing altered cells.
2. Types of cells in CM immunity
   a) Ag specific cells- T cells
   b) Ag non-specific cells macrophage, neutrophils, nk cells, and eosinophils.
3. The activities of the cells are dependent on the local concentration of various cytokines

Not on ppt.

What would be the result of someone having a missing thymus?

1. effector cells that direct cytotoxic activity that eliminate foreign and altered self cells by mounting a cytotoxic reaction that lyses the target.

a) two subcategories: ag specific Cytotoxic T Lymphocytes (CTLs) and nonspecific NK and macrophages.

2. Ag specfic effector CD4+ T cells that mediated delayed-type hypersensitivity reactions.

What distinguishes an effector t cell

from a naive t cell?

Which t cell would activate faster and why?

1) Naive T cell went through double positive selection and are mature, but have not been exposed to an antigen. An effector t cell have been stimulated by antigen and have memory.

2) Effector t cell would activate faster, because it has more adhesion molecules expressed on their cell to allow it to attach to target cells.

What are three properties of how CTLs and CD4+ Th1+ Th2 cells are different from Tc and and naive helper t cells?

What C45 isoforms are found on each cell and what is the purpose?

1. CTLs and CD4+ are easier to activate
2. express more cell adhesion molecules
3. production of soluble and membrane effector molecules (Cytokines and FasL)
4. exibit different trafficking patterns.

Naive T cells express CD45RA and Effector T cells express CD45RO; associate better with the TCR complex and its coreceptor, CD4 and CD8.

[image]

It is the generation of CTLs via Tc cell activation (aka CTL-Precursors/CTL-P aka Naive T cell) are class I MHC restricted.

a. Licensing requires signal 1 from TCR, costimulatory signal (CD28-B7) and IL-2 and requires the involvement of TH1 (CTL-P does not interact w/ TH1 directly only through dendritic cell that does not need to be on the same cell, but can be in close proximity.)

[image]

1. Effector CTLs recognize Ag (CTL-P is stimulated, now an effector)

2. Steps to destroy target cell

a. Conjugate formation: Increase IL-2 and LFA-1 and ICAM on infected cells, get golgi rearrangement to move granules of CTL to the site of conjugation. 

b. Membrane Attack: grains will move inside to target side and form pores into infected cells cause DNA fragmentation and apoptosis.

c. CTL dissociation

d. Target cell destruction

[image]

[image]

Describe the CTL-mediated killing on target cells using the four steps and describe it including what is expressed.

What happens if CTLs are lacking perforin?

Conjugate formation: TCR-CD3 complex binds to Ag-MHC I (integrins on CTL and ICAM on target) LFA-1 on CTL membrane binds to ICAs on target cellmembrane which brings it to a high affinity state.

Membrane Attack: repositioning of cytoplasmic granules toward the target cell and release the granules (perforin and proteases/granzymes)

CTL Dissociation: downshift in integrin (LFA-1) affinity

Target Cell destruction: cascade of reactions initiated by granzymes; fragmentation of DNA via apoptatic pathway.

2. T cells that lack perforin go through the FASL pathway.

1. cytokine IL-2 (cIL-2) controls the activation stage.

2. Declined: nonspecific damage is minimized, because there are healthy cells around. Reduction of IL-2 induces Th1 and CTLs undergo apoptosis to terminate immune response.

Describe what is going on in this photo.

[image]

CTLs move close to infected cell via conjugation.

1. release granules with perforin. The tight binding increase calcium via IP3.

2. Granules are released with perforin and cause lysis

3. granzymes will also be released to break down DNA.

Describe what is occuring in the Fas pathway? When is this pathway used?

[image]

1. Fas Ligand (FasL) on CTLs interact with Fas on target cells which are associated with Fat-associated protein with death domain (FADD).

2. FasL/FAS/FADD associated with procaspase (proteolytic clevage to become active) to convert to caspase 8 and initiates an apoptotic casapse cascade.

3a Caspase 8 associates with procaspase 3 and becomes active caspase

4a then undergoes Apoptosis

3b. Caspase associates with the mitochondria and release cytochrome c which attaches to a comple with caspase 9 and Apaf 1.

4b. Caspase 9/Apaf1/cytochrome C associate with procaspase 3 and becomes caspase 3

5b. undergoes apopotosis

1. non MHC restricted: Natural killer cells, neutrophils, macrophage, and eosinophils

2.  Antibody dependent cell mediated cytotoxicity. (ADCC)

 - bind FC region of AB on target cell (make ab to specific cell and bind to target cell then DC will recognize and bind and will do the same as TCL, release granules)

   - release lytic enzymes (perforin, TNF)

Natural killer cells secrete: granzymes perforin, and TNF

Eosinophil secrete: lytic enzymes and perforin

Macrophage: lytic enzyme, TNF

nautrophill: lytic enzymes

What is the function of natural killer cells and what substances are used to induce the function?

Do they need activation?

What regulates their activities?

1. Fn: Lysis of tumor cells and virus infected cells via perforin induced pore formation, granzymes and TNF. FasL pathway also can be used

2. Activation is not needed

3. Regulation it is not restricted to Ag/MHC. Receptors can either send activation or inhibitory signals to NK. Able to distinguish healthy cells from infected cells by the balance of activating and inbitory signals.

- generated in the bone marrow

- have CD2 and IL-2 receptor like T cells

- do not express Rag, No gene rearrangement

- Have CD16 (FC receptor) like monocytes

- no thymic development.

How are opposing signals used in how cytotoxic activity of natural killer cells are restricted to altered self cells?

[image]

MHC class I on a normal cell binds to inhibitory signal that blocks the kill signal of the ligand of the normal cell that is attached to the activating receptor of the NK.

Usually when a cell is infected by a virus it decreases the expression of MHC I and it does not inhibit the signal to kill, inducing the NK to kill.

1. Delayed-type hypersensitivity (DTH)

   - due to a subset of Th1 cells

2. release cytokines that produce localized inflammatory response.

3. Can cause some tissue damage, but is usually minimal.

    - if not stopped can be quite severe, why tissue rejection occurs

4. first seen against M. tuberculosis

    - seen in a bacteria first and not in a virus.