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 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 TCR.
Exogenous antigens are antigens that enter from outside the body such as bacteria, fungi, protozoa, and free viruses.
The first signal for the activation of a naive B lymphocyte occurs when B-cell receptors on the surface of the B lymphocyte bind epitopes of antigens having a corresponding shape. (A second signal is also needed for the activation of the naive B lymphocyte. This is provided when a component of the complement system called C3b binds to the microbial surface. C3b is subsequently degraded to C3d which, in turn, binds to a complement receptor called CR2 on the surface of the B lymphocyte. This step is not shown in this series.)
Once bound, the antigen is engulfed, placed in a phagosome, and degraded with lysosomes. During this process, protein antigens are broken down into a series of peptide epitopes. These peptides eventually bind to grooves in MHC-II molecules that are then transported to the surface of the B lymphocyte.
The TCRs and CD4 molecules on effector CD4 (T4) lymphocytes bind to the MHC-II molecules with bound peptide epitope on the B lymphocyte. This enables the effector CD4 (T4) lymphocytes to produce cytokines such as interleukin-2, interleukin-4, interleukin-5, and interleukin-6.
Collectively these cytokines:
1. Enable activated B lymphocytes to proliferate.
2. Stimulate activated B lymphocytes to synthesize and secrete antibodies.
3. Promote the differentiation of B lymphocytes into antibody-secreting plasma cells.
4. Enable antibody producing cells to switch the class or isotype of antibodies being produced.
In this series, a naïve B lymphocyte will become activated and subsequently present antigens to an effector CD4 (T4) lymphocyte.
The first of the two animations illustrates the binding of peptide epitopes from exogenous antigens to MHC-II molecules by a B lymphocyte.
Slides 1 and 2 show a virus binding to a B-cell receptor on a B lymphocyte where the virus is engulfed and placed in a phagosome.
Slides 3 and 4 show a lysosome fusing with the phagosome and the degradation of the virus.
In slides 5 and 6, viral proteins are shown being degraded by cellular proteases into a series of peptides within the phagolysosome.
Slides 7 and 8 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.
In slides 9 and 10, the MHC-II molecules with bound Ii chain are shown being transported to the Golgi complex and placed in vesicles.
Slides 11 and 12 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 13 and 14 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 naïve CD4 (T4) lymphocytes with TCRs and CD4 molecules having a complementary shape.
The second of the two animations illustrates an effector CD4 (T4) lymphocyte recognizing epitope–MHC-II on an activated B lymphocyte.
Slides 1 and 2 show an effector CD4 (T4) lymphocyte using its TCR and CD4 molecule to bind to a complementary-shaped MHC-II molecule with attached peptide epitope on an activated B lymphocyte.
Slides 3 and 4 show the binding of costimulatory molecules such as CD40 and B7 on the B lymphocyte with their complementary ligands on the effector CD4 (T4) lymphocyte in order to stabilize the cell-to-cell interaction.
In slides 5 and 6, the effector CD4 (T4) lymphocytes are shown producing cytokines that enable the activated B lymphocyte to proliferate, differentiate into antibody-secreting B lymphocytes and plasma cells, and switch classes of the antibodies being made.
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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