In contrast to the morphologically distinct cells of the innate immune system, lymphocytes of the adaptive immune system generally look-alike except for size, ranging from small (4 to 7 ?m) to medium (7 to 11 ?m) to large (11 to 15 ?m). Lymphocytes may be broadly categorized by the antigen-specific receptors they generate through gene rearrangement and by the organs in which they develop. These cells may be likened to the soldiers of the adaptive immune system.
Like soldiers, they often display combinations of additional surface molecules that serve essentially as molecular “badges” of rank and function. Also, cells of the adaptive immune response undergo “basic training” in specialized training centers (thymus or bone marrow), “bivouac” in specialized areas (spleen, lymph nodes, and lymphocyte accumulations), may be “promoted” (differentiation), and are transported from one anatomic site to another via the bloodstream or in their own lymphatic circulatory system.
The immune system must be able to distinguish its own molecules, cells, and organs (self) from those of foreign origin (nonself). The innate immune system does this by expressing, on the surfaces of its cells, germline-encoded pattern recognition receptors (PRRs) that recognize structures on potentially invasive organisms (see Chapter 5). The adaptive immune system, on the other hand, uses somatically generated epitope-specific T-cell and B-cell receptors (TCRs and BCRs).
These receptors are created anew and randomly within each individual T and B lymphocyte by gene recombination prior to antigen encounter (more about this in Chapter 8). No two individuals, even identical twins, have identical adaptive immune systems. Lymphocytes are usually defined by where they undergo “basic training”: in the thymus (thymus-derived lymphocytes or T cells and natural killer T or NKT cells) or in the bone marrow (B lymphocytes or B cells). They are also defined by the type of receptors they display on their cell surfaces: TCR (T cells and NKT cells), BCR or immunoglobulins (B cells), or neither (natural killer or NK cells).
A. Thymus-derived cells
T cells are the key players in most adaptive immune responses. They participate directly in immune responses as well as orchestrating and regulating the activities of other cells. T cells arise from hematopoietic stems cells in the bone marrow. Immature T cells called prothymocytes migrate to the thymus, where, as thymocytes, they develop TCRs and are screened for their ability to distinguish self from nonself.
Although most thymocytes fail the screening process and are eliminated, those that pass scrutiny and survive are able to further differentiate and mature to become thymus-derived lymphocytes or T cells and enter the circulation. The developmental pathways for T cells are discussed in greater detail in Chapter 9. Although T cells show a wide diversity in adaptive immune function (see Chapters 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18 and 19), all can be identified by the presence of the CD3 (cluster of differentiation 3) molecule that is associated with the TCR on the T-cell surface. Two other CD molecules are also used to identify CD3+ T-cell subsets, CD4 and CD8, and to readily distinguish their potential immune function.
1. CD4+ T cells
These cells account for approximately two-thirds of mature CD3+ T cells. CD4 molecules displayed on the surfaces of these T cells recognize a nonpeptide-binding portion of MHC class II molecules (Fig. 7.1). As a result, CD4+ T cells, also known as helper T (Th) cells, are “restricted” to the recognition of pMHC class II complexes.
Figure 7.1. Comprising approximately two-thirds of all T lymphocytes, CD4+ T cells are the workhorses of the adaptive immune system.
They display T-cell receptors (TCRs), associated CD3 signaling complex molecules, and CD4 molecules on their cell surfaces.
2. CD8+ T cells
CD8+ T cells account for approximately one-third of all mature CD3+ T cells. CD8 molecules displayed on the surfaces of these T cells recognize the nonpeptide-binding portion of MHC class I molecules. As a result, CD8+ T cells are “restricted” to the recognition of pMHC I complexes (Fig 7.2).
Functionally, CD8+ T cells are also known as cytotoxic T (Tc) and some act as suppressor T (Ts) cells. Tc cells identify body cells that are infected with intracellular organisms, such as viruses and intracellular bacteria, and eliminate the cells harboring these organisms. Ts cells function to downregulate and thus control adaptive immune responses.
Figure 7.2. Approximately one-third of the T cells are found in peripheral blood, CD8+ T cells display T-cell receptors (TCRs), associated CD3 molecules, and CD8 dimers on their cell surfaces.
B. Bone marrow–derived cells
Not all lymphocytes of bone marrow origin are destined for thymic education. Certain cells of lymphoid lineage remain and develop within the bone marrow and are the precursors of immunoglobulin-producing lymphocytes. These bone marrow–derived lymphocytes, also known as B lymphocytes or B cells, synthesize immunoglobulin and display it on their surfaces, where it functions as their BCR. Plasma cells are derived from differentiated, mature B cells and both synthesize and secrete immunoglobulin.
1. B cells
B cells arise from pluripotent hematopoietic stem cells in the bone marrow. They do not migrate to the thymus but develop within the bone marrow (Fig. 7.3). B cells arise from two distinct lineages: B-1 and B-2 cells. So named because they are the first to develop embryologically; B-1 cells are a self-renewing population that dominates the plural and peritoneal cavities. In contrast, conventional or B-2 cells arise during and after the neonatal period, are continuously replaced from the bone marrow, and are widely distributed throughout the lymphoid organs and tissues.
Each B cell is specific, that is, it produces immunoglobulin of only one antibody specificity that recognizes only one epitope. Like T cells, it is the extreme diversity among B cells, each producing a single form of immunoglobulin, that generates the overall diversity of the immunoglobulin (or antibody) response (Fig 7.3).
Figure 7.3. Bone marrow–derived lymphocytes or B cells synthesize immunoglobulin molecules that are displayed on their cell surface.
On the surface, they function as the B-cell epitope-specific receptor (BCR). BCR-associated Ig? and Ig? molecules signal the cell when an epitope is bound by the BCR.
2. Plasma cells
Plasma cells derive from terminally differentiated B cells and are immunoglobulin-producing and immunoglobulin-secreting cells. They cease to use immunoglobulin as a membrane receptor and instead secrete it into the fluids around the cells. Plasma cells, with increased size and metabolic activity, are factories that produce large quantities of immunoglobulin during their short life span of less than 30 days. They are characterized by basophilic cytoplasm, a nucleus that has a stellate (starlike) pattern within it, and nonstaining Golgi (Fig. 7.4).
Figure 7.4. Plasma cells are terminally differentiated B cells that both synthesize and secrete immunoglobulin.
Anatomically distinguishable from lymphocytes, their cytoplasm reflects increased ribosomes and endoplasmic reticulum. Immunoglobulin molecules are assembled within their (nonstaining) Golgi prior to export to the fluids surrounding the cell.
C. Natural killer cells
Approximately 5% to 10% of peripheral blood lymphocytes lack both T-cell (CD3) and B-cell (surface immunoglobulin) markers. These cells are known as natural killer (NK) cells to reflect their ability to kill certain virally infected cells and tumor cells without prior sensitization (see Chapters 4 and 5). Their granular appearance is caused by the presence of cytoplasmic granules containing perforin and granzyme that can be released to damage the membranes of the cells they attack. NK cells develop within the bone marrow and lack TCR produced by rearrangement of TCR genes (see Chapter 8).
However, they do bear another set of receptors called killer activation receptors (KARs) and killer inhibition receptors (KIRs) that allow them to recognize host cells that might need to be destroyed (Fig. 7.5, left). In addition, a unique subset of T cells, designated NKT because they share some functional characteristics with NK cells, develop within the thymus and express a rearranged TCR of extremely limited repertoire (Fig. 7.5, right). Unlike conventional T cells, NKT cells respond to lipids, glycolipids, or hydrophobic peptides presented by a specialized, nonclassical MHC class I molecule, CD1d, and secrete large amounts of cytokines, especially interleukin-4 (IL-4).
Figure 7.5. Natural killer (NK) and natural killer T (NKT) cells bridge both adaptive and innate immune systems.
NK cells are chaaracteristically large granular lymphocytes that express neither TCRs nor BCRs and bear receptors for stress molecules (killer activation receptors or KARs) and for MHC class I molecules (killer inhibition receptors or KIRs). Unlike NK cells, NKT cells express low levels of TCRs with extremely limited repertoires.