CELLS OF THE IMMUNE SYSTEM

The cells of the immune system exchange information by releasing cytokines (signaling molecules) and by physically contacting each other to recognize membranebounded molecules. These cells may be subdivided into four major categories: antigen presenting cells (APCs), natural killer cells (NK cells), clones of T lymphocytes (T cells), and clones of B lymphocytes (B cells). A clone is a small population of identical cells, each of which is capable of recognizing and responding to one specific (or very closely related) epitope.

Antigen-Presenting Cells

Antigen-presenting cells (APCs), macrophages, and B lymphocytes possess class II major histocompatibility complex molecules (MHC II molecules), whereas all other nucleated cells possess MHC I molecules. In humans, MHC molecules are also referred to as human leukocyte antigen molecules (HLA molecules).

•Macrophages and some other APCs can degrade antigens into epitopes, small highly antigenic peptides 7 to 11 amino acids long.

Each epitope is attached to an MHC II molecule, and this complex is placed on the external aspect of its cell membrane.

The MHC II-epitope complex is recognized by the T-cell receptor (TCR) in conjunction with the CD4

molecule of the TH1 or TH2 cells, a process known as MHC II restriction.

•B cells have the capability of acting as APCs and pre-

sent their MHC II-epitope complex to TH1 cells (discussed below).

APCs, specifically macrophages, produce and release a variety of cytokines that modulate the immune response. These include

interleukin 1, which stimulates T helper cells and self-activated macrophages, as well as

prostaglandin E2, which attenuates some immune responses.

Cytokines, such as interferon-g, released by other lymphoid cells as well as by macrophages, enhance the phagocytic and cytolytic avidity of macrophages.

Lymphocytes

The lymphocyte, the principal cell of lymphoid tissue, is a key controller responsible for the proper functioning of the immune system. Lymphocytes may be subdivided, according to function, into three categories: null cells, T lymphocytes, and B lymphocytes.

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Null Cells

Null cells are composed of two categories of cells, namely, stem cells and NK cells (although some immunologists prefer not to use this classification system and avoid the null cell category).

•Stem cells are undifferentiated cells that will give rise to the various cellular elements of blood cell lineage,

•NK cells are cytotoxic cells that are responsible for the destruction of certain categories of foreign cells. NK cells resemble cytotoxic T cells, but they do not have to enter the thymus to become mature killer cells; instead, they are immunocompetent as soon as they leave the bone marrow.

These cells kill virally altered cells and tumor cells in a nonspecific manner, and they are not MHC restricted.

NK cells also recognize and become activated by the Fc portions of those antibodies that are bound to cell surface epitopes.

Once activated, NK cells release perforins and fragmentins to kill these decorated cells by a procedure known as antibody-dependent cell-mediated cytotoxicity.

Perforins assemble as pores within the plasmalemma of target cells, contributing to necrotic cell death, whereas fragmentins drive the target cell into apoptosis, directed cell death.

NK cells also possess integral proteins known as killer activating receptors that have an affinity to specific proteins on the cell membranes of nucleated cells.

To protect self cells from this response, NK cells also possess additional transmembrane proteins, known as killer-inhibitor receptors, that avoid the killing of healthy cells.

T Lymphocytes (T cells)

T cells are immunoincompetent until they enter the cortex of the thymus. Here, under the influence of the cortical environment, they express their T cell receptors (TCRs) and cluster of differentiation markers (CD2, CD3, CD4, CD8, and CD28) and become immunocompetent.

•Once immunocompetent, the T cells enter the medulla of the thymus or are killed if they are committed against the self.

•In the medulla, they will lose either their CD4 or their CD8 markers and thus develop into CD8+ or CD4+ cells, respectively.

•These cells enter into blood vessels of the medulla to become members of the circulating population of lymphocytes. They do not produce antibodies; instead, they function in the cell-mediated immune response.

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•There are several categories of T cells that are responsible not only for the cell-mediated immune response but also for facilitating the humorally mediated response of B cells to thymic-dependent antigens.

•To be able to perform their functions, T cells possess characteristic integral membrane proteins on their cell surfaces.

One of these is the T-cell receptor (TCR), which has the capability of recognizing that particular epitope for which the cell is genetically programmed.

T cells can recognize only those epitopes that are bound to MHC molecules present on the surface of antigen-presenting cells.

Thus, T cells are said to be MHC restricted. There are three general categories of T cells: naïve T cells, memory T cells, and effector T cells.

It is the T lymphocytes that participate in the graft rejection phenomenon and in the elimination of virally transformed cells. There are three general categories of T cells: naïve T cells, memory T cells, and effector T cells.

•Naïve T cells are immunologically competent and possess CD45RA molecules on their plasma membrane, but they have to become activated before they can function as T cells.

Activation involves the interaction of the naïve T cell’s TCR-CD3 complex with the MHC-epitope complex of APCs, as well as the interaction of the T cell’s CD28 molecule with the antigen-presenting cell’s B7 molecule.

The activated naïve T cell enters the cell cycle and forms memory T cells and effector T cells.

•Memory T cells are immunocompetent cells that are the progeny of activated T cells that undergo mitotic activity during an antigenic challenge. These cells are long-lived, circulating cells that are added to and increase the number of cells of the original clone. It is this increase in the size of the clone that is responsible for the anamnestic response (a more rapid and more intense secondary response) against another encounter with the same antigen.

•Effector T cells. The categories of effector T cells are

T helper cells (TH cells), cytotoxic T lymphocytes (CTLs, T killer cells), regulatory T cells (T reg cells), and natural T killer cells.

T Helper cells are all CD4+ cells and are subdivided into four categories: TH0, TH1, TH2, and TH17 cells.

TH0 cells enter the cell cycle and can give rise to TH1 and TH2 cells.

TH1 cells produce and release the cytokines interleukin 2, interferon-γ, and tumor necrosis

factor-α. TH1 cells have an essential role in the initiation of the cell-mediated immune response and in the destruction of intracellular pathogens.

TH2 cells produce and release interleukins 4, 5, 6, 9, 10, and 13, which, among other roles, induce B cells to proliferate and differentiate into plasma

cells that produce antibodies. Additionally, TH2 cells initiate the reaction against parasites and mucosal infections.

TH17 cells are proinflammatory cells that are responsible for some autoimmune diseases, such as rheumatoid arthritis and multiple sclerosis. TH17 cells produce

-interleukin 17 (IL-17), which acts on stromal and other cells to initiate the inflammatory process, and

-interleukin 21 (IL-21), which acts in an autocrine fashion to induce the proliferation of TH17 cells.

Cytotoxic T lymphocytes are CD8+ cells. Upon contacting the proper MHC-epitope complex displayed by APCs and having been activated by interleukin 2, these cells undergo mitosis to form numerous cytotoxic T lymphocytes (CTLs).

These newly formed cells kill foreign and virally transformed self cells by secreting perforins and fragmentins and by expressing CD95L (the death ligand) on their plasmalemma, which activates CD95 (death receptor) on the target cell’s plasma membrane, which drives the target cell into apoptosis.

T reg cells are CD4+ cells that function in the suppression of the immune response. There are two types of T regulatory cells:

natural T reg cells, whose TCR binds to APCs and thus suppresses the immune response, and

inducible T reg cells that release cytokines that inhibit the formation of TH1 cells.

Natural T killer cells are similar to NK cells, but they have to enter the cortex of the thymus to be immunocompetent. They are unusual because they have the ability to recognize lipid antigens.

Once a T lymphocyte becomes activated by the presence of an antigen, it releases cytokines, substances that activate macrophages, attract them to the site of antigenic invasion, and enhance their phagocytic capabilities. Frequently, T lymphocytes also assist B lymphocytes to amplify and modulate their immune response. The major interactions among T cells, B cells, and antigen-presenting cells are illustrated in Graphics 9-3 to 9-5.

B Lymphocytes (B Cells)

B lymphocytes (B cells) are formed and become immunocompetent in the bone marrow (bursa of Fabricius in birds). They enter the general circulation, establish clones