Step Perspective, Volume 5, Number 1; A Publication Of The Seattle Treatment Education Project - February 1993
Emily Platt, PhD

T and B lymphocytes and macrophages begin their development in the bone marrow then migrate elsewhere to complete the process. B cells and monocytes (the precursor of macrophage cells), mature mostly in the bone marrow with final steps occurring in the spleen. T cells leave the bone marrow to do most of their maturation in the thymus (which is why they're called "T" cells), and then complete maturing in the spleen. After release from the spleen, B and T cells continue their migratory existence, traveling through the blood to sites of inflammation and to lymph nodes (this requires that these cells cross the cellular lining of blood vessels), eventually returning to the circulation via lymphatic vessels. Monocytes also migrate through the blood to sites of inflammation. Once these cells leave the blood and enter tissues, they mature fully and are termed macrophages ("big eaters").

Lymphocytes play a major role in maintaining a healthy immune system in an individual. The immune system is composed of two complementary arms: 1) humoral, which is carried out by B cells, and 2) cell-mediated immunity, which is performed by T cells. Humoral immunity refers to the production of antibodies by mature, antibody-secreting B cells. Antibodies function by inactivating invading organisms and marking them for engulfment and digestion by phagocytic cells, such as macrophages. Cell-mediated immunity refers to the helper and killer (or cytotoxic) functions of T cells. Helper T cells play a role in stimulating antibody production by B cells. It is this subset of T cells (known as CD4 T cells) that are infected by HIV-1. Killer cells (called CD8 T cells) have the ability to recognize and kill cells that have been infected with a virus. Incidentally, the terms CD4 and CD8 refer to a kind of protein (cell differentiation antigen) that appear on the cell surface of T cells during their development. Therefore, mature cytotoxic T cells possess the CD8 protein, but not the CD4 protein at their cell surface, while the converse is true for helper CD4 cells. The CD4 and CD8 molecules also determine the type of antigen to which a T cell can respond.

The two subsets of T cells (helpers, CD4+ & and killers, CD8+) are activated to perform their respective functions when they encounter an antigen. Antigens are foreign molecules (often proteins), that can induce an immune response. antigen-presenting cells (APC) degrade the foreign protein molecules into small fragments (peptides). The peptides are presented to T cells as entities bound to the cell surface molecules of the APC. There are two types of cell surface molecules which can bind antigen: Major Histocompatibility complex (MHC) Class I and MHC class II. Antigens that live inside cells or outside cells can be presented to T cells. Virtually all cells are able to present antigens synthesized inside cells, as occurs upon virus infection. such antigens are presented bound to MHC Class I molecules. Specialized antigen presenting cells (such as B cells, macrophages, and dendritic cells), engulf extra cellular foreign proteins, process them into small fragments, and present them at the cell surface bound to MHC Class II molecules. The T cell antigen receptor (TCR) present at the cell surface of both CD4 and CD8 T cells recognizes processed antigen bound to the MHC molecules. The CD8 protein at the surface of cytotoxic T cells recognizes antigens which are bound by MHC Class I molecules, allowing the CD8 cells to kill virally infected cells. thus, CD8 T cells are termed MHC Class I restricted in their recognition of antigens. T cells bearing the CD4 protein recognize antigens in the context of MHC Class II. Antigen stimulated CD4 T cells, in turn, induce antibody production by B cells.

In addition to its normal biological function in determining Class II restriction of CD4 T cells, the CD4 molecule also acts as the viral receptor for HIV-1. The gp120 envelope protein of HIV-1 allows the virus to recognize and bind to the CD4 molecule, permitting the virus to fuse with the plasma membrane and enter the cell. It is well documented that infection with HIV-1 causes a decline in CD4 T cells over time. While no definitive cause has been uncovered to explain CD4 decline, there are numerous hypotheses. These include the killing of uninfected CD4 cells which have free gp120 bound to their surface, autoimmune response, formation of syncytia (masses of fused cells) between infected and uninfected cells, and inappropriate responses of infected CD4 T cells to antigenic stimulation.

Recent reports in medical literature suggest that antigen presentation to CD4 T cells by dendritic cells may play an important role in spreading HIV-1 infection. As mentioned earlier, dendritic cells present antigen complexed with MHC Class II. They also reside in numerous locations in the body, such as blood, lymph nodes, and skin. Since MHC Class II APC come into close contact with CD4 T cells, they have a great potential to spread HIV-1 if they themselves become infected. Additionally, antigen presentation stimulates CD4 T cells to proliferate and activated CD4 T cells allow productive HIV-1 infection (i.e. integration of the viral genome into the host genome with subsequent virus production by the infected cell). Thus, the microenvironment in which antigen presentation occurs can promote the spread of HIV-1 infection. It has been demonstrated in the laboratory that mixing HIV-1 exposed, washed, dendritic cells with CD4 T cells, can cause a cytopathic (cell killing), productive infection of CD4 T cells upon the normal clustering of CD4 T cells around the antigen presenting dendritic cells. This may mimic pathogenic processes in the lymph node. In fact, electron microscopic studies of lymph node biopsies from people with AIDS have demonstrated HIV-1 particles associated with follicular dendritic cells, while other studies have revealed the degeneration of germinal centers of lymph nodes, the region of antigen presentation by follicular dendritic cells.
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