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Antigen Presentation #3: MHC Class I

Antigen Presentation

Presentation by Epithelial Cells

Consider: Under what circumstances would any cell in the body need to initiate an immune response?

Here, I’m using epithelial cells as an example, however, every cell in the body has the ability to present antigens on MHC Class I. In fact, it is a normal, continuous process that the cells cannot fail in without consequence.

While professional APCs process and present antigens that they have phagocytized, other cells divert a small amount of the total protein they make towards MHC I presentation. This allows the immune system to constantly observe these cells and ensure that they are not suffering gross mutations or infections. Most of the time, cells produce normal, ‘self’ proteins against which there are no T Cells (due to negative selection – see Lymphocyte Development).

In the event that MHC I expression is subverted, these cells are presumed to be infected and will be targeted for killing by special cells called Natural Killers, or NK Cells.

If a Non-Self antigen is presented by MHC I, these are recognized by CD8 T Cells. Like the reactions between APCs and CD4 T Cells, cells expressing MHC I + Non-Self Ag engage T Cells via their unique TCRs. The only difference is that these T Cell : Presenting-cell complexes are stabilized by CD8 molecules on CD8+ Killer T Cells.

ImageThe result of this binding is the activation and proliferation of Killer T Cells that will turn upon and kill the presenting cells by releasing perforin and granzymes that perforate target cells and trigger apoptosis (cellular suicide).

Keep in Mind the Big Picture!

To summarize with an example:

  1. Host cells are infected with a virus
  2. The virus replicates within the host cell, producing viral proteins in the process
  3. Some of these proteins are diverted to proteases that digest them and load the antigen fragments onto MHC I molecules
  4. The MHC I +Ag is transported to the plasma membrane to ‘present’ Ag
  5. MHC I +Ag is recognized by a T Cell bearing an TCR specific for the MHC+Ag complex. This interaction is stabilized by CD8 binding to MHC I.
  6. If a stable interaction is formed, the T Cell will become activated, meaning it will proliferate and secrete perforin and granzyme toward the presenting cell
  7. Perforin and Granzyme will lead to the apoptotic death of the presenting cell
  8. By killing the infected cells, the infection can be stopped before spreading farther in the body.

A CD8 T Cell (the smaller cell) killing a virally infected host cell:

Image

 
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Posted by on December 8, 2013 in Uncategorized

 

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Antigen Presentation #2: B Cells

Antigen Presentation

Presentation by B Cells

Before thinking about B Cells presenting antigen, first recall that B Cells are lymphocytes bearing antigen receptors on their surface called B Cell Receptors (BCRs). These BCRs have been randomized during development such that every B Cell can theoretically bind a unique antigen. See Lymphocyte Development for a refresher on this if you need it.  The major function of B Cells is to make antibody that is nearly identical to its receptor protein, which will be secreted and can then bind to antigens of the same shape.

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B Cell with specific BCR engages an antigen on a bacterium (Left). After activation this B Cell will become a Plasma Cell secreting antibody with identical specificity as the original BCR (Right).

A major distinction between B Cell phagocytosis and that by Macrophages is that B Cells only take up materials they have bound with their BCRs, while macrophages take up material indiscriminately. The reason for this, of course, is that B Cells are gearing up to produce antibody, and the best way to ensure this antibody will bind anything of use is if only B Cells bearing specific BCRs known to bind antigen are activated. Macrophages have no antigen-specific receptors, so this specificity is not required by those cells. The membrane bound BCR is exactly the same molecule as secreted antibody – except for the small portion that anchors the BCR to the membrane.

Like macrophages, B cells are ‘professional’ antigen presenting cells (APCs) that take up exogenous antigen, break it down within lysosomes and present the resulting peptide fragments within MHC Class II Molecules. As with other professional APCs, this is intended to pick up foreign, invasive particles for present them to T cells to elicit a specific immune response.

ImageJust by binding to antigen with their BCRs, the B Cell will become (at least partially) activated, stimulating proliferation of this cell and processing/presentation of antigen as indicated above. In order to complete its activation, this B Cell must receive ‘help’ from T Cells capable of binding the presented antigen in the context of MHC II. Because T Cells have also been selected for ‘Non-Self’ exclusivity, this provides additional insurance that this B Cell was truly activated by a ‘Non-Self’ antigen.  The MHC II :: TCR + CD4 interaction between the antigen-presenting B Cell and the helper T Cell results in activation of the T Cell, that immediately gives activation signals (cytokines) back to the B Cell.

 

Keep in Mind the Big Picture!

To summarize with an example:

  1. A bacteria gets into the host
  2. B Cells with BCRs capable of binding any part of that bacteria catch ahold of it
  3. These B Cells gobble up the bacteria (endocytosis)
  4. Inside the B Cell, the bacteria is killed and broken into a bunch of little pieces
  5. The little bacteria pieces are picked up by MHC II molecules
  6. MHC II molecules move to the cell surface and ‘present’ antigen
  7. T Cells with TCRs capable of binding this bacteria piece within MHC II, do so
  8. These T Cells become activated, proliferate and produce activation factors (cytokines)
  9. These activation factors trigger the B Cell to go on proliferating and changing into Plasma Cells.

10. Plasma Cells no longer make BCR on the surface, they make a soluble form of that BCR, called Antibody, and spew that forth in great amounts.

11. Antibody can coat, gum up, and signal the disposal of bacteria all over the body.

Resting and Activated T Cells from “Immune System History” by Dr. Harry Louis E. Trinidad 
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All that ER expansion is to accommodate the heavy load of secreted protein this cell will churn out.

 

 

 
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Posted by on December 8, 2013 in Uncategorized

 

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Three posts on Antigen Presentation

Having recently finished teaching a semester of microbiology ending with my favorite topic, immunology, I thought I would provide some summaries of three different types of antigen presentation:

1. Presentation of antigen by macrophages (MHC II + Ag) to CD T Cells (TCR + CD4) resulting in the activation of CD4+ Helper T Cells

2. Presentation of antigen by B Cells (MHC II + Ag) to CD T Cells (TCR + CD4) resulting in the activation of CD4+ Helper T Cells – specifically capable of activating B Cells that have ‘seen’ and taken up antigens that bind to their unique BCRs.

3. Presentation of antigen by Epithelial Cells (MHC I + Ag) to CD T Cells (TCR + CD8) resulting in the activation of Cytotoxic T Lymphocytes (CTLs) that will kill cells presenting this antigen. All Cells bear MHC I, enabling them to present endogenous, intercellular antigens such as infecting virus particles.

 
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Posted by on December 8, 2013 in Uncategorized

 

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