Major histocompatibility (MHC) molecules enable T lymphocytes to recognize epitopes of antigens and discriminate self from nonself. Unlike B-cell receptors on B lymphocytes that are able to directly bind epitopes on antigens, the T-cell receptors (TCRs) of T lymphocytes can only recognize epitopes, typically short chains of amino acids called peptides, after they are bound to MHC molecules. There are two classes of MHC molecules: MHC-I and MHC-II. MHC-I presents epitopes to CD8 (T8) lymphocytes while MHC-II presents epitopes to CD4 (T4) lymphocytes.
MHC-II molecules are designed to enable CD4 (T4) lymphocytes to recognize epitopes of exogenous antigens and discriminate self from nonself.
MHC-II molecules are:
· made by antigen-presenting cells (APCs), such as dendritic cells, macrophages, and B lymphocytes;
· possess a deep groove that can bind peptide epitopes, typically 10 to 30 amino acids long but with an optimum length of 12 to 16 amino acids, from exogenous antigens; and
· present MHC-II–peptide complexes to CD4 (T4) lymphocytes that have a complementary-shaped T-cell receptor (TCR).
Exogenous antigens are antigens that enter from outside the body such as bacteria, fungi, protozoa, and free viruses.
Macrophages, found throughout the body, function as phagocytes and as antigen-presenting cells. Macrophages primarily 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. Macrophages engulf microorganisms and other antigens and degrade them with their lysosomes. Peptides from microbial proteins are then bound to a groove of unique molecules called MHC-II molecules produced by macrophages, dendritic cells, and B lymphocytes. The peptide epitopes bound to the MHC-II molecules are then put on the surface of the macrophage where they can be recognized by complementary-shaped TCRs and CD4 molecules on an effector CD4 (T4) lymphocyte. This interaction leads to the activation of that macrophage.
Functionally, there are probably many different types or subpopulations of effector CD4 (T4) lymphocytes based on the cytokines they produce. Chronic immune reactions are typically dominated by three primary types:
· Th1cells produce cytokines that promote cell-mediated immunity, especially against intracellular microbes, by activating macrophages and cytotoxic T lymphocytes, promote the production of antibodies that promote phagocytosis, and block the production of Th2cells;
· Th2 cells produce cytokines that promote responses against helminths and allergens, promote the production of antibodies that neutralize microbes and toxins, promote the removal of microbes in mucosal tissues, and block the production of Th1 cells; and
· Th17 cells induce inflammatory reactions rich in neutrophils.
A major function of Th1 cells is to both promote phagocytosis of microbes and the killing of intracellular microbes by macrophages. An activated Th1 lymphocyte binds to a peptide–MHC-II complex on a macrophage by way of its TCR and CD4 molecule. Costimulatory molecules such as CD40L on the Th1 cell then bind to CD40 on a macrophage.
The Th1 lymphocyte then secretes the cytokine interferon-gamma (IFN-gamma) that binds to IFN-gamma receptors on the macrophage. The IFN-gamma activates the macrophage enabling it to produce more hydrolytic lysosomal enzymes, nitric oxide, and toxic oxygen radicals that destroy the microorganisms within the phagosomes and phagolysosomes.
In the first animation in this series, a macrophage is shown processing an exogenous antigen for eventual presentation to a Th1 lymphocyte.
Slides 1 and 2 show a protein antigen being degraded by cellular proteases into a series of peptides within a phagolysosome.
Slides 3 and 4 show MHC-II molecules being synthesized in the endoplasmic reticulum and transported to the Golgi complex. Once assembled within the endoplasmic reticulum, a protein called the invariant chain (Ii) attaches to the peptide-binding groove of the MHC-II molecules and in this way prevents peptides designated for binding to MHC-I molecules within the endoplasmic reticulum from attaching to the MHC-II.
Slides 5 and 6 show the MHC-II molecules with bound Ii chain being transported to the Golgi complex and placed in vesicles.
Slides 6 and 7 show the vesicles containing the MHC-II molecules fusing with the peptide-containing phagolysosome. As the Ii chain is removed, the peptides are now free to bind to the grooves of the MHC-II molecules.
Finally, slides 8 and 9 show MHC-II molecules with bound peptides being transported to the cytoplasmic membrane where they become anchored. Here, the peptide and MHC-II complexes can be recognized by an effector Th1 cell possessing T-cell receptors and CD4 molecules with a complementary shape.
In the second animation in this series, the activation of a macrophage by a Th1 lymphocyte will be shown.
Slide 1 shows a macrophage with engulfed bacteria within a phagolysosome.
Slides 2 and 3 show an activated Th1 lymphocyte binding to a peptide–MHC-II complex on a macrophage by way of its TCR and CD4 molecules.
Slide 4 shows the Th1 lymphocyte producing IFN-gamma.
Slides 5 and 6 show the Th1 lymphocyte secreting IFN-gamma molecules that bind to IFN-gamma receptors on the macrophage. The IFN-gamma activates the macrophage enabling it to produce more hydrolytic lysosomal enzymes, nitric oxide, and reactive oxygen species that destroy the microorganisms within the phagosomes and phagolysosomes.
Macromedia Flash Professional 8 was used in constructing this animation. Illustrations were drawn using Adobe Illustrator 10.0.3 and imported into Flash 8.
References.
1. Abbas, A. K., A. H. Lichtman, and S. Pillai. 2007. Cellular and molecular immunology, 6th ed. Saunders/Elsevier Publishing, Philadelphia, PA.
2. Delves, P. J., S. J. Martin, D. R. Burton, and I. M. Roitt. 2006. Roitt’s essential immunology, 11th ed. Blackwell Publishing, Malden, MA.
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