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12.3B: Antigen-Presenting Cells (APCs)

Skills to Develop

  1. Describe the overall function of antigen-presenting cells (APCs) such as dendritic cells, macrophages, and B-lymphocytes in terms of the following:
    1. how they "process" exogenous antigens
    2. how they "process" endogenous antigens
    3. the types of MHC molecule to which they attach peptides
    4. the role of proteasomes in the binding of peptides from endogenous antigens by MHC-I molecules.
    5. the role of lysosomes in the binding of peptides from exogenous antigens by MHC-II molecules.
    6. the types of cells to which they present peptides
  2. Name the primary type of cell that functions as an antigen-presenting cell to naive T4-lymphocytes and naive T8-lymphocytes.
  3. State the role of T4-effector cells in activating macrophages.
  4. State the role of T4-effector cells in the proliferation and differentiation of activated B-lymphocytes.

We will now take a look at antigen-presenting cells (APCs), which include dendritic cells, macrophages, and B-lymphocytes. APCs express both MHC-I and MHC-II molecules and serve two major functions during adaptive immunity: (1.) they capture and process antigens for presentation to T-lymphocytes, and (2) they produce signals required for the proliferation and differentiation of lymphocytes. We will now take a closer look at our three primary groups of APCs: dendritic cells, macrophages, and B-lymphocytes.

Dendritic Cells

As learned in Unit 5, most dendritic cells are derived from monocytes and are referred to as myeloid dendritic cells. They are located under the surface epithelium of the skin and the surface epithelium of the mucous membranes of the respiratory tract, genitourinary tract, and the gastrointestinal tract. They are also found throughout the body's lymphoid tissues and in most solid organs.

In these locations, in their immature form, they are attached by long cytoplasmic processes. Upon capturing antigens through pinocytosis and phagocytosis and becoming activated by inflammatory cytokines, the dendritic cells detach from their initial site, enter lymph vessels, and are carried to regional lymph nodes (Figure 1). Activation of the dendritic cell promotes its expression chemokine receptor CCR7 that enables the dendritic cell to migrate towards the chemokine CCL21 produced by lymphoid tissues. By the time the dendritic cells enter the lymph nodes, they have matured and are now able to present antigen epitopes to the ever-changing populations of naive T8-lymphocytes and naive T4-lymphocytes located in the T-cell area of the lymph nodes.

Figure 1: Structure of a Lymph Nodes Antigens enter lymph nodes through afferent lymphoid vessels. Antigen-presenting dendritic cells, B-lAntigens enter lymph nodes through afferent lymphoid vessels. Antigen-presenting dendritic cells enter the lymph node through afferent lymphatic vessels while naive B-lymphocytes, and naive T-lymphocytes enter through high endothelial venules. Non-activated and effector lymphocytes leave the lymph node through efferent lymphatic vessels. Naive B-lymphocytes become activated, proliferate, and differentiate into plasma cells in the germinal centers of lymphoid follicles while naive T-lymphocytes become activated, proliferate and differentiate into T-effector lymphocytes in the T-cell area.

The primary function of dendritic cells, then, is to capture and present protein antigens to naive T-lymphocytes. (Naive lymphocytes are those that have not yet encountered an antigen.) Since dendritic cells are able to express both MHC-I and MHC-II molecules, they are able to present antigens to both naive T8-lymphocytes and naive T4-lymphocytes.

These interactions enable the naiveT4-lymphocyte or T8-lymphocyte to become activated, proliferate, and differentiate into effector lymphocytes. (Effector lymphocytes are lymphocytes that have encountered an antigen, proliferated, and matured into a form capable of actively carrying out immune defenses.)

1. MHC-II presentation of protein antigens to naive T4-lymphocytes

a. MHC-II presentation of exogenous antigens to naive T4-lymphocytes

Immature dendritic cells take in protein antigens for attachment to MHC-II molecules and subsequent presentation to naive T4-lymphocytes by:

1. Receptor-mediated phagocytosis, e.g., PAMPs binding to endocytic PRRs, IgG or C3b attachment of microbes to phagocytes during opsonization (see Fig. 2).

2. Macropinocytosis, a process where large volumes of surrounding fluid containing microbes are engulfed. This also enables dendritic cells to take in some encapsulated bacteria that might resist classical phagocytosis (see Fig. 3).

The binding of microbial PAMPs to the PRRs of the immature dendritic cell activates that dendritic cell and promotes production of the chemokine receptor CCR7 that directs the dendritic cell into local lymphoid tissue. Following maturation, the dendritic cell can now present protein epitopes bound to MHC molecules to all the various naive T-lymphocytes passing through the lymphoid system (See Fig. 4 and Fig. 5).

The MHC-II molecules bind peptide epitopes from exogenous antigens and place them on the surface of the dendritic cell (see Fig. 6). Here the MHC-II/peptide complexes can be recognized by complementary shaped TCRs and CD4 molecules on naive T4-lymphocytes (see Fig. 7).

b. MHC-II cross-presentation of endogenous antigens to naive T4-lymphocytes

While most dendritic cells present exogenous antigens to naive T4-lymphocytes, certain dendritic cells are capable of cross-presentation of endogenous antigens to naive T4-lymphocytes. In this way, T4-lymphocytes can play a role in defending against both exogenous and endogenous antigens. This is done via autophagy, the cellular process whereby the cell's own cytoplasm is taken into specialized vesicles called autophagosomes (See Fig. 8). The autophagosomes subsequently fuse with lysosomes containing proteases that will degrade the proteins in the autophagosome into peptides. From here, the peptides are transported into the vesicles containing MHC-II molecules where they can bind to the MHC-II groove, be transported to the surface of the denritic cell, and interact with the TCRs and CD4 molecules of naive T4-lymphocytes (See Fig. 8).

2. MHC-I presentation of protein antigens to naive T8-lymphocytes

Immature dendritic cells take in protein antigens for attachment to MHC-I molecules and subsequent presentation to naive T8-lymphocytes.

a. MHC-I presentation of endogenous antigens to naive T8-lymphocytes

During the replication of viruses and intracellular bacteria within their host cell, as well as during the replication of tumor cells, viral, bacterial, or tumor proteins are degraded into a variety of peptide epitopes by cylindrical organelles called proteasomes. The body's own cytosolic proteins are also degraded into peptides by proteasomes.

These peptide epitopes are then attached to a groove of MHC-I molecules that are then transported to the surface of that cell where they can be recognized by a complementary-shaped T-cell receptor (TCR) and a CD8 molecule, a co-receptor, on the surface of either a naive T8-lymphocyte or a cytotoxic T-lymphocyte (CTL). The TCRs recognize both the foreign peptide antigen and the MHC molecule. TCRs, however, will not recognize self-peptides bound to MHC-I. As a result, normal cells are not attacked and killed.

MHC-I molecule with bound peptide on the surface of antigen-presenting dendritic cells ; see Fig. 9 can be recognized by a complementary-shaped TCR/CD8 on the surface of a naive T8-lymphocyte to initiate cell-mediated immunity (see Fig. 10).

b. MHC-I cross-presentation of exogenous antigens to naive T8-lymphocytes

While most dendritic cells present endogenous antigens to naive T8-lymphocytes, certain dendritic cells are capable of cross-presentation of exogenous antigens to naive T8-lymphocytes. In this way, T8-lymphocytes can play a role in defending against both exogenous and endogenous antigens. There are two proposed mechanisms for cross-presentation of exogenous antigens to T8-lymphocytes:

1. The dendritic cell engulfs the exogenous antigen and places it in a phagosome which then fuses with a lysosome to form a phagolysosome. The antigen is partially degraded in the phagolysosome where proteins are translocated into the cytoplasm where they are processed into peptides by proteasomes, enter the endoplasmic reticulum, and are bound to MHC-I molecules (see Fig. 11).

2. The dendritic cell engulfs the exogenous antigen and places it in a phagosome which then fuses with a lysosome to form a phagolysosome. The protein antigens are degraded into peptides within the phagolysosome which then directly fuses with vesicles containing MHC-I molecules to which the peptides subsequently bind (see Fig. 12).

In addition, dendritic cells are very susceptible to infection by many different viruses. Once inside the cell, the viruses become endogenous antigens in the cytosol. Once in the cytosol, the viral proteins from the replicating viruses are degraded into peptides by proteasomes where they subsequently bind to MHC-I molecules.

The binding of microbial PAMPs to the PRRs of the immature dendritic cell activates that dendritic cell and promotes production of the chemokine receptor CCR7 that directs the dendritic cell into local lymphoid tissue. Following maturation, the dendritic cell can now present protein epitopes bound to MHC molecules to all the various naive T-lymphocytes passing through the lymphoid system.

To view an electron micrograph of a dendritic cell presenting antigen to T-lymphocytes, #1 see the Web page for the University of Illinois College of Medicine.

To view an electron micrograph of a dendritic cell presenting antigen to T-lymphocytes, #2 see the Web page for the University of Illinois College of Medicine.

Exercise: Think-Pair-Share Questions

Dendritic cells are located under the surface epithelium of the skin and the surface epithelium of the mucous membranes of the respiratory tract, genitourinary tract, and the gastrointestinal tract. They are also found throughout the body's lymphoid tissues and in most solid organs. Once activated, dendritic cells are attracted to chemokines produced by the lymphoid system.

Why is this essential for effective adaptive immunity ?

For a Summary of Key Surface Molecules and Cellular Interactions of Antigen-Presenting Dendritic Cells, see Fig. 13.

Macrophages

As we learned in Unit 5, when monocytes leave the blood and enter the tissue, they become activated and differentiate into macrophages. Those that have recently left the blood during inflammation and move to the site of infection are sometimes referred to as wandering macrophages. In addition, the body has macrophages already stationed throughout the tissues and organs of the body. These are sometimes referred to as fixed macrophages. Many fixed macrophages are part of the mononuclear phagocytic (reticuloendothelial) system. They, along with B-lymphocytes and T-lymphocytes, are found supported by reticular fibers in lymph nodules, lymph nodes, and the spleen where they filter out and phagocytose foreign matter such as microbes. Similar cells derived from stem cells, monocytes, or macrophages are also found in the liver (Kupffer cells), the kidneys (mesangial cells), the brain (microglia), the bones (osteoclasts), the lungs (alveolar macrophages), and the gastrointestinal tract (peritoneal macrophages).

The primary function of macrophages, then, is to capture and present protein antigens to effector T-lymphocytes. (Effector lymphocytes are lymphocytes that have encountered an antigen, proliferated, and matured into a form capable of actively carrying out immune defenses.)

The MHC-II molecules bind peptide epitopes from exogenous antigens and place them on the surface of the macrophages. Here the MHC-II/peptide complexes can be recognized by complementary shaped T-cell receptors (TCRs) and CD4 molecules on an effector T4-lymphocytes ; see Fig.14.

Effector T4-lymphocytes called TH1 cells coordinate immunity against intracellular bacteria and promote opsonization by macrophages.

1. They produce cytokines such as interferon-gamma (IFN-?) that promote cell-mediated immunity against intracellular pathogens, especially by activating macrophages that have either ingested pathogens or have become infected with intracellular microbes such as Mycobacterium tuberculosis, Mycobacterium leprae, Leishmania donovani, and Pneumocystis jiroveci that are able to grow in the endocytic vesicles of macrophages. Activation of the macrophage by TH1 cells greatly enhances their antimicrobial effectiveness (see Fig. 14).

2. They produce cytokines that promote the production of opsonizing and complement activating IgG that enhances phagocytosis (see Fig. 15).

3. They produce receptors that bind to and kill chronically infected cells, releasing the bacteria that were growing within the cell so they can be engulfed and killed by macrophages.

4. They produce cytokines such as tumor necrosis factor-alpha (TNF-a) that promote diapedesis of macrophages.

5. They produce the chemokine CXCL2 to attract macrophages to the infection site.

 

There is growing evidence that monocytes and macrophages can be “trained” by an earlier infection to do better in future infections, that is, develop memory. It is thought that microbial pathogen-associated molecular patterns (PAMPs) binding to pattern-recognition (PRRs) on monocytes and macrophages triggers the cell’s epigenome to reprogram or train that cell to react better against new infections.

For a Summary of Key Surface Molecules and Cellular Interactions of Antigen-Presenting Macrophages, see Fig. 16.

B-lymphocytes

Like all lymphocytes, B-lymphocytes circulate back and forth between the blood and the lymphoid system of the body. B-lymphocytes are able to capture and present peptide epitopes from exogenous antigens to effector T4-lymphocytes. The MHC-II molecules bind peptide epitopes from exogenous antigens and place them on the surface of the B-lymphocytes. Here the MHC-II/peptide complexes can be recognized by complementary shaped T-cell receptors (TCRs) and CD4 molecules on an effector T4-lymphocytes (see Fig. 17). This interaction eventually triggers the effector T4-lymphocyte to produce and secrete various cytokines that enable that B-lymphocyte to proliferate and differentiate into antibody-secreting plasma cells (see Fig. 18).

For a Summary of Key Surface Molecules and Cellular Interactions of Antigen-Presenting B-Lymphocytes, see Fig. 19.

Summary

  1. Antigen-presenting cells (APCs) include dendritic cells, macrophages, and B-lymphocytes.
  2. APCs express both MHC-I and MHC-II molecules and serve two major functions during adaptive immunity: they capture and process antigens for presentation to T-lymphocytes, and they produce signals required for the proliferation and differentiation of lymphocytes.
  3. Most dendritic cells are derived from monocytes and are referred to as myeloid dendritic cells and  are located under the surface epithelium of the skin, the mucous membranes of the respiratory tract, genitourinary tract, and the gastrointestinal tract, and throughout the body's lymphoid tissues and in most solid organs.
  4. The primary function of dendritic cells is to capture and present protein antigens to naive T-lymphocytes which enables the naïve T4-lymphocytes or T8-lymphocytes to become activated, proliferate, and differentiate into effector cells.
  5. Naïve lymphocytes are B-lymphocytes and T-lymphocytes that have not yet reacted with an epitope of an antigen.
  6. Dendritic cells use MHC-II molecules to present protein antigens to naïve T4-lymphocytes and MHC-I molecules to present protein antigens to naïve T8-lymphocytes.
  7. When monocytes leave the blood and enter the tissue, they become activated and differentiate into macrophages.
  8. When functioning as APCs, macrophages capture and present peptide epitopes from exogenous antigens to effector T4-lymphocytes.
  9. Effector lymphocytes are lymphocytes that have encountered an antigen, proliferated, and matured into a form capable of actively carrying out immune defenses.
  10. B-lymphocytes mediate antibody production.
  11. When functioning as APCs, B-lymphocytes are able to capture and present peptide epitopes from exogenous antigens to effector T4-lymphocytes.
  12. To activate naïve T4-lymphocytes, dendritic cells engulf exogenous antigens, place them in a phagosome, degrade protein antigens into peptides via lysosomes, bind those peptides to MHC-II molecules and transport them to the surface of the dendritic cell where they can be recognized by the T-cell receptors and CD4 molecules of naïve T4-lymphocytes.
  13. To activate naïve T8-lymphocytes, dendritic cells degrade endogenous protein antigens into peptides via their proteasomes, bind those peptides to MHC-I molecules and transport them to the surface of the dendritic cell where they can be recognized by the T-cell receptors and CD8 molecules of naïve T8-lymphocytes.

Contributors

  • Dr. Gary Kaiser (COMMUNITY COLLEGE OF BALTIMORE COUNTY, CATONSVILLE CAMPUS)