The immune system is composed of many interdependent cell types that collectively protect the body from bacterial, parasitic, fungal, viral infections and from the growth of tumor cells. Many of these cell types have specialized functions. The cells of the immune system can engulf bacteria, kill parasites or tumor cells, or kill viral-infected cells. Often, these cells depend on the T helper subset for activation signals in the form of secretions formally known as cytokines, lymphokines, or more specifically interleukins. The purpose of this article is to review the organs, cell types and interactions between cells of the immune system as a commentary on their importance and interdependence on the T helper subset. Such an understanding may help comprehend the root of immune deficiencies, and perceive potential avenues that the immune system can be modulated in the case of specific diseases.
The Organs of the Immune System
Bone Marrow -- All the cells of the immune system are initially derived from the bone marrow. They form through a process called hematopoiesis. During hematopoiesis, bone marrow-derived stem cells differentiate into either mature cells of the immune system or into precursors of cells that migrate out of the bone marrow to continue their maturation elsewhere. The bone marrow produces B cells, natural killer cells, granulocytes and immature thymocytes, in addition to red blood cells and platelets.

Thymus -- The function of the thymus is to produce mature T cells. Immature thymocytes, also known as prothymocytes, leave the bone marrow and migrate into the thymus. Through a remarkable maturation process sometimes referred to as thymic education, T cells that are beneficial to the immune system are spared, while those T cells that might evoke a detrimental autoimmune response are eliminated. The mature T cells are then released into the bloodstream.

Spleen -- The spleen is an immunologic filter of the blood. It is made up of B cells, T cells, macrophages, dendritic cells, natural killer cells and red blood cells. In addition to capturing foreign materials (antigens) from the blood that passes through the spleen, migratory macrophages and dendritic cells bring antigens to the spleen via the bloodstream. An immune response is initiated when the macrophage or dendritic cells present the antigen to the appropriate B or T cells. This organ can be thought of as an immunological conference center. In the spleen, B cells become activated and produce large amounts of antibody. Also, old red blood cells are destroyed in the spleen.

Lymph Nodes -- The lymph nodes function as an immunologic filter for the bodily fluid known as lymph. Lymph nodes are found throughout the body. Composed mostly of T cells, B cells, dendritic cells and macrophages, the nodes drain fluid from most of our tissues. Antigens are filtered out of the lymph in the lymph node before returning the lymph to the circulation. In a similar fashion as the spleen, the macrophages and dendritic cells that capture antigens present these foreign materials to T and B cells, consequently initiating an immune response.
The Cells of the Immune System
T-Cells -- T lymphocytes are usually divided into two major subsets that are functionally and phenotypically (identifiably) different. The T helper subset, also called the CD4+ T cell, is a pertinent coordinator of immune regulation. The main function of the T helper cell is to augment or potentiate immune responses by the secretion of specialized factors that activate other white blood cells to fight off infection.

Another important type of T cell is called the T killer/suppressor subset or CD8+ T cell. These cells are important in directly killing certain tumor cells, viral-infected cells and sometimes parasites. The CD8+ T cells are also important in down-regulation of immune responses. Both types of T cells can be found throughout the body. They often depend on the secondary lymphoid organs (the lymph nodes and spleen) as sites where activation occurs, but they are also found in other tissues of the body, most conspicuously the liver, lung, blood, and intestinal and reproductive tracts.

Natural Killer Cells -- Natural killer cells, often referred to as NK cells, are similar to the killer T cell subset (CD8+ T cells). They function as effector cells that directly kill certain tumors such as melanomas, lymphomas and viral-infected cells, most notably herpes and cytomegalovirus-infected cells. NK cells, unlike the CD8+ (killer) T cells, kill their targets without a prior "conference" in the lymphoid organs. However, NK cells that have been activated by secretions from CD4+ T cells will kill their tumor or viral-infected targets more effectively.

B Cells -- The major function of B lymphocytes is the production of antibodies in response to foreign proteins of bacteria, viruses, and tumor cells. Antibodies are specialized proteins that specifically recognize and bind to one particular protein that specifically recognize and bind to one particular protein. Antibody production and binding to a foreign substance or antigen, often is critical as a means of signaling other cells to engulf, kill or remove that substance from the body.

Granulocytes or Polymorphonuclear (PMN) Leukocytes -- Another group of white blood cells is collectively referred to as granulocytes or polymorphonuclear leukocytes (PMNs). Granulocytes are composed of three cell types identified as neutrophils, eosinophils and basophils, based on their staining characteristics with certain dyes. These cells are predominantly important in the removal of bacteria and parasites from the body. They engulf these foreign bodies and degrade them using their powerful enzymes.

Macrophages -- Macrophages are important in the regulation of immune responses. They are often referred to as scavengers or antigen-presenting cells (APC) because they pick up and ingest foreign materials and present these antigens to other cells of the immune system such as T cells and B cells. This is one of the important first steps in the initiation of an immune response. Stimulated macrophages exhibit increased levels of phagocytosis and are also secretory.

Dendritic Cells -- Another cell type, addressed only recently, is the dendritic cell. Dendritic cells, which also originate in the bone marrow, function as antigen presenting cells (APC). In fact, the dendritic cells are more efficient apcs than macrophages. These cells are usually found in the structural compartment of the lymphoid organs such as the thymus, lymph nodes and spleen. However, they are also found in the bloodstream and other tissues of the body. It is believed that they capture antigen or bring it to the lymphoid organs where an immune response is initiated. Unfortunately, one reason we know so little about dendritic cells is that they are extremely hard to isolate, which is often a prerequisite for the study of the functional qualities of specific cell types. Of particular issue here is the recent finding that dendritic cells bind high amount of HIV, and may be a reservoir of virus that is transmitted to CD4+ T cells during an activation event.
The Immune Response
An immune response to foreign antigen requires the presence of an antigen-presenting cell (APC), (usually either a macrophage or dendritic cell) in combination with a B cell or T cell. When an APC presents an antigen on its cell surface to a B cell, the B cell is signalled to proliferate and produce antibodies that specifically bind to that antigen. If the antibodies bind to antigens on bacteria or parasites it acts as a signal for pmns or macrophages to engulf (phagocytose) and kill them. Another important function of antibodies is to initiate the "complement destruction cascade." When antibodies bind to cells or bacteria, serum proteins called complement bind to the immobilized antibodies and destroy the bacteria by creating holes in them. Antibodies can also signal natural killer cells and macrophages to kill viral or bacterial-infected cells.

If the APC presents the antigen to T cells, the T cells become activated. Activated T cells proliferate and become secretory in the case of CD4+ T cells, or, if they are CD8+ T cells, they become activated to kill target cells that specifically express the antigen presented by the APC. The production of antibodies and the activity of CD8+ killer T cells are highly regulated by the CD4+ helper T cell subset. The CD4+ T cells provide growth factors or signals to these cells that signal them to proliferate and function more efficiently. This multitude of interleukins or cytokines that are produced and secreted by CD4+ T cells are often crucial to ensure the activation of natural killer cells, macrophages, CD8+ T cells, and PMNs is listed in the chart below.

One possible line of therapy is to reintroduce some of these cytokines to people who have severe immune deficiencies. This approach can be tricky because large amounts of any particular cytokine can have serious side effects. Furthermore, their half-life in the body is usually relatively short. Another short-coming of "replacement" therapy is that many cytokines will activate the CD4+ T cells or macrophages harboring HIV, and this could lead to faster rates of HIV production by those cells. Theoretically, this could lead to progression of HIV rather than prophylaxis against opportunistic infections. However, recent progress in this area warrants attention and further study. Lack of interleukin-2 (IL-2) is believed to be one of the major causes of immune deficiency in AIDS. In recent studies where low dose IL-2 was administered to people with HIV, CD4 T cell counts rose, as did anti-viral specific immunity, and natural killer cell cytotoxic activity. Administration of IL-3 to people with HIV is currently under investigation as a treatment for HIV associated cytopenia (low production of cells from the bone marrow). IL-4, a cytokine that activates B cells and also has inhibitory effects on the production of TNF, is currently under investigation for the treatment of Kaposi's sarcoma. GM-CSF (granulocyte macrophage-colony stimulating factor), another growth factor produced by CD4+ T cells, is under investigation for the treatment of decreased white blood cell production for people on ganciclovir therapy.

Additionally, IFN-gamma (gamma interferon) is under investigation as a treatment for people with PCP. Hopefully, these studies will lead to cures for certain opportunistic infections, or for use in inhibiting HIV production and ultimately saving lives.