THE ADAPTIVE IMMUNE SYSTEM

I. INTRODUCTION

B. MAJOR CELLS AND KEY CELL-SURFACE MOLECULES INVOLVED IN ADAPTIVE IMMUNE RESPONSES

1. MHC Molecules

Fundamental Statements for this Learning Object:

1. MHC molecules enable T-lymphocytes to recognize epitopes and discriminate self from non-self.
2.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.
3.MHC-I presents epitopes to T8-lymphocytes; MHC-II presents epitopes to T4-lymphocytes
.
4.
MHC-I molecules are designed to enable the body to recognize infected cells and tumor cells and destroy them with cytotoxic T-lymphocytes or CTLs. (CTLs are effector defense cells derived from naïve T8-lymphocytes.)
5.
MHC-I molecules are made by all nucleated cells in the body; bind peptide epitopes typically from endogenous antigens; present MHC-I/peptide complexes to naive T8-lymphocytes and cytotoxic T-lymphocytes possessing a complementary-shaped T-cell receptor or TCR.
6. Through the process of cross-presentation, some antigen-presenting dendritic cells can cross-present epitopes of exogenous antigens to MHC-I molecules for eventual presentation to naive T8-lymphocytes.
7. Endogenous antigens are proteins found within the cytosol of human cells and include viral proteins produced during viral replication, proteins produced by intracellular bacteria, proteins that have escaped into the cytosol from the phagosome of phagocytes such as antigen-presenting cells, and tumor antigens produced by cancer cells.
8. 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 resulting peptide epitopes are then attached to MHC-I molecules that are then transported to the surface of that cell.
9. Exogenous antigens are antigens that enter from outside the body such as bacteria, fungi, protozoa, and free viruses.
10. MHC-II molecules are made by antigen-presenting cells or APCs, such as dendritic cells, macrophages, and B-lymphocytes; bind peptide epitopes typically from exogenous antigens; and present MHC-II/peptide complexes to naive T4-lymphocytes or effector T4-lymphocytes that have a complementary shaped T-cell receptor or TCR.
11. Through the process of cross-presentation, some antigen-presenting dendritic cells can cross-present epitopes of endogenous antigens to MHC-II molecules for eventual presentation to naive T4-lymphocytes.
12. Exogenous antigens enter antigen-presenting macrophages, dendritic cells, and B-lymphocytes through phagocytosis, and are engulfed and placed in a phagosome where protein antigens from the microbe are degraded by proteases into a series of peptides. These peptides are then attached to MHC-II molecules that are then put on the surface of the APC.


LEARNING OBJECTIVES FOR THIS SECTION


Adaptive (acquired) immunity refers to antigen-specific defense mechanisms that take several days to become protective and are designed to remove a specific antigen (def). This is the immunity one develops throughout life. There are two major branches of the adaptive immune responses: humoral immunity and cell-mediated immunity.

1. humoral immunity (def): humoral immunity involves the production of antibody molecules in response to an antigen (def) and is mediated by B-lymphocytes.

2. cell-mediated immunity (def): Cell-mediated immunity involves the production of cytotoxic T-lymphocytes, activated macrophages, activated NK cells, and cytokines in response to an antigen (def) and is mediated by T-lymphocytes.

We will now take a look at major cells and key cell-surface molecules involved in adaptive immune responses, starting with MHC molecules.


The Roles of MHC Molecules In Adaptive Immune Responses

MHC molecules enable T-lymphocytes (def) to recognize epitopes (def) of antigens (def) and discriminate self from non-self. 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 (see Fig. 1).

The MHC genes are the most polymorphic genes (def) in the human genome, possessing many alleles for each gene. The MHC genes are co-dominantly expressed so that an individual expresses the alleles inherited from each parent. In this way, the number of MHC molecules that bind peptide for presentation to T-lymphocytes is maximized. In addition, each MHC molecule is able to bind a wide variety of different peptides (def), both self-peptides and foreign peptides.

There are two classes of MHC molecules: MHC-I and MHC-II.

The expression of MHC molecules is increased by cytokines produced during both innate immune responses and adaptive immune responses. Cytokines such as interferon-alpha, interferon-beta, interferon-gamma, tumor necrosis factor increase the expression of MHC-I molecules, while interferon-gamma is the main cytokine to increase the expression of MHC-II molecules.

 

a. MHC-I molecules

MHC-I molecules (def) are designed to enable the body to recognize infected cells and tumor cells and destroy them with cytotoxic T-lymphocytes or CTLs (def). CTLs are effector (def) defense cells derived from naive T8-lymphocytes (def).

MHC-I molecules are:

Endogenous antigens are proteins found within the cytosol (def) of human cells. Examples of endogenous antigens include:

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 (def). The body's own cytosolic proteins are also degraded into peptides by proteasomes.

These peptide epitopes (def) are then attached to a groove of MHC-I molecules (def) 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 (def), 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 (see Fig. 2). TCRs, however, will not recognize self-peptides bound to MHC-I. As a result, normal cells are not attacked and killed.

MHC-I molecules are coded for by three MHC-I genes, HLA-A, HLA-B, and HLA-C. As mentioned above, however, there are many different alleles for each gene that a person inherits. In this way, the number of MHC-I molecules that bind peptides for presentation to T-8 lymphocytes is maximized. The expression of MHC-I molecules on all cell types is increased by the cytokines interferon-alpha (IFN-α) and interferon-beta (IFN-β).

 

b. MHC-II molecules

MHC-II molecules (def) are designed to enable T4-lymphocytes to recognize epitopes (def) of exogenous antigens (def) and discriminate self from non-self.

MHC-II molecules are:

Exogenous antigens (def) are antigens that enter from outside the body, such as bacteria, fungi, protozoa, and free viruses. These exogenous antigens enter macrophages, dendritic cells, and B-lymphocytes through phagocytosis. The microbes are engulfed and placed in a phagosome (def) which then fuses with lysosomes (def). Following this fusion, the phagolysosome becomes acidified. Acidification, in turn, activates the proteases within the phagolysosome enabling protein antigens from the microbe to be degraded into a series of short peptides (def). These peptide epitopes (def) are then attached to MHC-II molecules (def) and are then transported to the surface of the antigen-presenting cell (APC) (see Fig. 7). (Certain dendritic cells, as discussed later, can also cross-present endogenous antigens to MHC-II molecules.)

Some pathogens, such as Mycobacterium tuberculosis, Mycobacterium leprae, and Leishmania, are able to grow in the endocytic vesicles of macrophages without being killed by lysosomes. These macrophages can, however, become activated by T4-effector lymphocytes (def) called TH1 cells and subsequently use intravesicular proteases to degrade the proteins from these pathogens into peptides for presentation to MHC-II molecules that pass through on their way to the cell surface.

Here the MHC-II molecules (def) with bound peptides can be recognized by a complementary-shaped T-cell receptor and a CD4 molecule (def), a co-receptor, on the surface of a T4-lymphocyte (see Fig. 8) . T4-lymphocytes are the cells the body uses to regulate both humoral immunity (def) and cell-mediated immunity (def).

MHC-II molecules are coded for by three MHC-II genes, HLA-DR, HLA-DP, and HLA-DQ. Interferon-gamma  (IFN- γ) increases the expression of both MHC-I and MHC-II molecules.

     

 

 

 


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