Organization of the immune-lymphatic system

The lymphatic system includes primary and secondary lymphoid organs.

The primary lymphoid organs produce the cell components of the immune system. They are (1) the bone marrow and (2) the thymus. The main cell type is the lymphocyte originated from a lymphoid stem cell in bone marrow (Figure 10-1).

Figure 10-1 Lineage origin of the lymphoid progeny within the context of hematopoiesis

The secondary lymphoid organs are the sites where immune responses occur. They include (1) the lymph nodes, (2) the spleen, (3) the tonsils, and (4) aggregates of lymphocytes and antigen-presenting cells in the lung (bronchial-associated lymphoid tissue [BALT] and the mucosa of the digestive tract (gut-associated lymphoid tissue [GALT] including Peyer’s patches). The lymphatic system is widely distributed because pathogens can enter the body at any point.

The main function of the lymphoid organs, as components of the immune system, is to protect the body against invading pathogens or antigens (bacteria, viruses, and parasites). The basis for this defense mechanism, or immune response, is the ability to distinguish self from nonself.

The two key cell components of the immune system are lymphocytes and accessory cells (Figure 10-2). Lymphocytes include two major cell groups: (1) B cells, responding to cell-free and cell-bound antigens; and (2) T cells, subdivided into two categories: helper T cells and cytolytic or cytotoxic T cells. T cells respond to cell-bound antigens presented by specific molecules.

Figure 10-2 Major cells participating in immune reactions

After leaving the two primary organs (bone marrow and thymus), mature B and T cells circulate in the blood until they reach one of the various secondary lymphoid organs (lymph nodes, spleen, and tonsils).

B and T cells can leave the bloodstream through specialized venules called high endothelial venules, so called because they are lined by tall endothelial cells instead of the typical squamous endothelial cell type.

The accessory cells include two monocyte-derived cell types: macrophages and dendritic cells. An example of a dendritic cell is the Langerhans cell found in the epidermis of the skin. A third type, the follicular dendritic cell, is present in lymphatic nodules of the lymph nodes. Follicular dendritic cells differ from ordinary dendritic cells in that they do not derive from a bone marrow precursor.

Before we start our discussion of the origin, differentiation, and interaction of lymphocytes and accessory cells, we will define the characteristics of the immune system. Then, we will be able to integrate the structural aspects of each major lymphatic organ with the specific characteristics of the immune responses.

Properties of adaptive or acquired immunity

Both humoral and cell-mediated immunity developed against foreign pathogens have the following characteristics:

Major histocompatibility complex and human leukocyte antigens

The presentation of antigens to T cells is carried out by specialized proteins encoded by genes in the major histocompatibility locus and present on the surface of antigen-presenting cells. Antigen-presenting cells survey the body, find and internalize antigens by phagocytosis, break them down into antigenic peptide fragments, and bind them to major histocompatibility complex (MHC) molecules (Figure 10-5) so that the antigen peptide fragment–MHC complex can be exposed later on the surface of the cells. The MHC gene locus expresses gene products responsible for the rejection of grafted tissue between two genetically incompatible hosts.

Figure 10-5 Structure of the T cell receptor and class I and II major histocompatibility complex (MHC)

There are two types of mouse MHC gene products: class I MHC and class II MHC. The class I MHC molecule consists of two polypeptide chains: an α chain, consisting of three domains (α₁, α₂, and α₃) encoded by the MHC gene locus, and β₂-microglobulin, not encoded by the MHC gene locus. Antigens are housed in a cleft formed by the α₁ and α₂ domains. CD8, a coreceptor on the surface of cytolytic T cells, binds to the α₃ domain of class I MHC.

Class II MHC consists of two polypeptide chains, an α chain and a β chain. Both chains are encoded by the MHC gene locus. The α₁ and β₁ domains form an antigen-binding cleft. CD4, a coreceptor on the surface of helper T cells, binds to the β domain of class II MHC. CD4 and CD8 are cell surface identifiers, members of the cluster of differentiation or designation (abbreviated as CD). See Box 10-B.

All nucleated cells express class I MHC molecules. Class II MHC molecules are restricted mainly to antigen-presenting cells (macrophages, dendritic cells, and B cells), stromal epithelial cells of the thymus, and endothelial cells.

The MHC-equivalent molecules in the human are designated human leukocyte antigens (HLAs). HLA molecules are structurally and functionally homologous to mouse MHC molecules and the gene locus is present on human chromosome 5 (β₂-microglobulin is encoded by a gene on chromosome 15).

The class I MHC locus encodes three major proteins in the human: HLA-A, HLA-B, and HLA-C. The class II MHC locus encodes HLA-DR (R for antigenically related), HLA-DQ, and HLA-DP (Q and P preceding R in the alphabet).

T cell receptor complex

In addition to MHC molecules, subsets of T cells have cell surface receptors that enable each of them to recognize a different antigen peptide–MHC combination. Antigen recognition involves an immunologic synapse mechanism consisting in the formation of stable antigen-presenting cell–T cell adhesiveness followed by an activating signaling cascade by T cells (see Box 10-C).

The receptor that recognizes specific antigenic peptides presented by class I and class II MHC molecules is the T cell receptor (TCR). TCR acts together with accessory cell surface molecules, called coreceptors, to stabilize the binding of antigen-presenting cells to T cells.

The TCR consists of two disulfide-linked transmembrane polypeptide chains: the α chain and the β chain (see Figure 10-5). A limited number of T cells have a TCR composed of γ and δ chains. Each α and β chain consists of a variable (Vα and Vβ) domain and a constant (Cα and Cβ) domain. When compared with the immunoglobulin molecule, the Vα and Vβ domains are structurally and functionally similar to the antigen-binding fragment (Fab) of immunoglobulins.

The TCR molecule is associated with two proteins, CD3 and ζ (not shown in Figure 10-5), forming the TCR complex. CD3 and ζ have a signaling role and are present in all T cells. CD3 contains the ITAM cytoplasmic domain previously mentioned as part of the B cell antigen receptor complex and involved in signaling functions.

CD4 and CD8 coreceptors

CD4 and CD8 are T cell surface proteins interacting selectively with class II MHC and class I MHC molecules, respectively. When the TCR recognizes an antigen bound to the cleft of MHC, CD4 or CD8 coreceptors cooperate in the activation of T cell function (see Figure 10-5).

CD4 and CD8 are members of the immunoglobulin (Ig) superfamily. In Chapter 1, Epithelium, we discussed the function and structure of cell adhesion molecules belonging to the Ig superfamily.

Members of the Ig superfamily have a variable number of extracellular Ig-like domains. The two terminal Ig-like domains of CD4 bind to the β₂ domain of the class II MHC (see Figure 10-5). The single Ig-like domain of CD8 binds to the α₃, domain of the class I MHC.

Thus, CD4⁺ helper T cells recognize antigens associated with class II MHC, and CD8⁺ cytolytic T cells (cytolytic thymus-derived lymphocytes [CTL]) respond to antigens presented by class I MHC (Figure 10-6).

Figure 10-6 General features of helper and cytolytic T cells

MHC molecules and adaptive immune responses

T cells are MHC-restricted. T cells are able to react against a foreign antigen fragment bound to their own (self-) MCH molecules and contribute to adaptive immune responses. T cells should not respond to self-antigen peptide fragments bound to self-MHC molecules. This lack of response is called self-tolerance. Developing T cells express unique TCRs generated by random rearrangement of a variety of gene segments. These randomly produced TCRs provide the diversity required to identify numerous foreign peptides.

During their maturation in the cortex of the thymus, T cells are selected to be self-MHC–restricted and self-tolerant. This selective process, known as positive selection, occurs only when self-MCH–restricted T cells are selected (see Figure 10-7). Negative selection takes place when T cells do not bind to any MHC or bind to the body’s tissue-specific antigens (self-molecules). We discuss later how a portfolio of self-antigens expressed in the thymus permits the elimination of autoreactive T cells by apoptosis. Only those T cells that can recognize foreign peptides and self-MHC survive, leave the thymus, and migrate into the secondary lymphoid organs.

Figure 10-7 Maturation of T cells involves changes in cell surface molecules

The cortex of the thymus contains branching and interconnected thymic cortical epithelial cells involved in the positive selection of T cells. The medulla of the thymus houses thymic medullary epithelial cells involved in the negative selection of potentially autoreactive T cells. Contact between MHC molecules on the thymic epithelial cell surfaces and TCRs of developing T cells is an important feature in positive selection. This is another example of the importance of the immunological synapse (see Box 10-C).

T cells developing in the thymus express specific cell surface molecules

Two major events take place in the thymus during T cell maturation: (1) a rearrangement of the gene-encoding protein components of the TCR and (2) the transient coexistence of TCR-associated coreceptors CD4 and CD8.

When precursor cells—derived from the bone marrow—enter the cortex of the thymus, they lack surface molecules typical of mature T cells. Because they still do not express CD4 and CD8, they are called “double-negative” T cells.

After interacting with thymic epithelial cells, double-negative T cells proliferate, differentiate, and express the first T cell–specific molecules: TCR and coreceptors CD4 and CD8.

TCR consists of two pairs of subunits: αβ chains or γδ chains (see Figure 10-3). Each chain can vary in sequence from one T cell to another. This variation is determined by the random combination of gene segments and has a bearing on which foreign antigen T cells can recognize.

Maturation of T cells proceeds through a stage where both CD4 and CD8 coreceptors and low levels of TCR are expressed by the same cell. These cells are known as “double-positive” T cells. Double-positive T cells can or cannot recognize self-MHC. Those cells that can recognize self-MHC eventually mature and express one of the two coreceptor molecules (CD4 or CD8) and become “single-positive” T cells. Double-positive cells that cannot recognize self-MHC fail positive selection and are discarded.

T cell-mediated immunity

When T cells complete their development in the thymus, they enter the bloodstream and migrate to the peripheral lymphoid organs in search of an antigen on the surface of an antigen-presenting cell.

Helper T cells contain both the TCR and CD4 coreceptor. Helper T cells recognize class II MHC on antigen-presenting cells.

There are two distinct subtypes of helper T cells derived from the same CD4⁺ T cell precursor: Th1 and Th2 cells.

Th1 cells participate in the regulation of immune responses caused by intracellular pathogens (viruses causing infections, certain bacteria, or single-cell parasites) with the significant participation of macrophages. Th1 cells produce interferon-γ, which can suppress the activity of Th2 cells.

Immune responses controlled by TH2 cells are observed in patients with helminthic (Greek helmins, worm) intestinal parasites. Th2 cells produce interleukin-4 (IL-4) and interleukin-13 (IL-13), among other cytokines, and determine the production of immunoglobulin E by plasma cells to activate the responses of mast cells, basophils, and eosinophils. The activation of macrophage responses is minimal in Th2-driven immune responses.

Cytolytic (or killer) T cells display both the TCR and CD8 coreceptor. Cytolytic T cells recognize class I MHC on antigen-presenting cells. We will return to the clinical significance of helper and cytolytic T cells when we discuss their involvement in the pathology of human immunodeficiency virus-type 1 (HIV-1) infection, allergy, and cancer immunotherapy.

How do helper T cells help?

Helper T cells are activated when they recognize the antigen peptide–class II MHC complex (Figure 10-8).

Figure 10-8 Helper T cells

In the presence of cells with antigen peptide bound to class II MHC, helper T cells proliferate by mitosis and secrete cytokines, also called interleukins. These chemical signals, in turn, attract B cells, which also have receptor molecules of single specificity on their surface (immunoglobulin receptor). Unlike helper T cells, B cells can recognize free antigen peptides without MHC molecules.

When activated by interleukins produced by the proliferating helper T cells, B cells also divide and differentiate into plasma cells secreting immunoglobulins, a soluble form of their receptors. Secreted immunoglobulins diffuse freely, bind to antigen peptides to neutralize them, or trigger their destruction by enzymes or macrophages.

Plasma cells synthesize only one class of immunoglobulin (several thousand immunoglobulin molecules per second; lifetime of a plasma cell is from 10 to 20 days). Five classes of immunoglobulins are recognized in humans: IgG, IgA, IgM, IgE, and IgD (see Box 10-D). Abnormal plasma cells may accumulate in bones and bone marrow, causing bone destruction and affecting the production of normal blood cells. This pathologic condition is called multiple myeloma (see Box 10-E).

Box 10-D Immunoglobulins

• An immunoglobulin (Ig) molecule or antibody is composed of four polypeptide chains: two identical light chains and two identical heavy chains. One light chain is attached to one heavy chain by a disulfide bond. The two heavy chains are attached to each other by disulfide bonds.

• Heavy and light chains consists of amino terminal variable regions that participate in antigen recognition (Fab region) and carboxyl terminal constant regions. The constant region (Fc region) of the heavy chains mediate effector functions.

• Immunoglobulins can be membrane-bound or secreted.

• Types of immunogloblins: IgA forms dimers linked by a J chain and participate in mucosal immunity. IgD is a receptor for antigens of inmature B cells. IgE participates in mast cell and basophil activation (degranulation). IgG is the most abundant immunogloblin and the only one to cross the placental barrier. It participates in opsonization, a mechanism that enhances phagocytosis of pathogens. IgM molecules normally exist as pentamers.