lymphocytes (B cells) get their name from the organ site where they were first identified and shown to develop in birds, namely the bursa of Fabricius. As discussed in Chapter 1, in mammals, the major site of B cell maturation is the bone marrow where hematopoietic stem cells differentiate into CLPs which further differentiate into different lymphocyte populations (see Figure 2.6). B cells develop in a clonal fashion and fully mature within the bone marrow environment. Ultimately, each B‐cell clone differentiates to generate antigen receptors (antibody) composed of immunoglobulin molecules that get expressed as transmembrane molecules. A typical antibody molecule is composed of four polypeptide chains: two identical heavy chains and two identical light chains (Figure 2.7) (see also Figure 1.2 and Chapter 6).
Mature B cells entering the periphery are endowed with hundreds of thousands of antigen‐specific immunoglobulin (Ig) molecules anchored within their plasma membranes. These are closely associated with signaling molecules (Igα and Igβ) to enable the B cell to communicate with the nucleus when the B cell binds to its specific antigen. Together, the plasma membrane‐bound immunoglobulin and Igα/Igβ) molecules make up the B cell receptor (BCR) complex (Figure 2.8). B‐cell signaling following antigen activation is discussed in Chapter 9.
Figure 2.4. (A) Overall and section views of the spleen. (B) Section of spleen. The yellow arrow indicates red pulp. The green arrow points to white pulp showing a splenic nodule with a germinal center.
Source: Photograph by Dr Susan Gottesman, SUNY Downstate College of Medicine, New York.
The molecular mechanisms associated with the generation of these multichain polypeptide are discussed in Chapter 9. In short, the genes encoding the antigen receptors are formed by recombination of DNA segments during B‐cell maturation resulting in the generation of millions of uniquely recombined receptor genes encoding protein chains that associate with each other to create BCRs. Once B cells fully mature, they clonally express these BCRs to manifest a highly diverse repertoire of antigen specificities. Individual B cells within a given clone (with millions of cells per clone) all express identical BCRs and, hence, they share the same antigen specificity.
Figure 2.5. (A) Section of lymph node. Arrows show flow of lymph and lymphocytes. (B) Section through a lymph node showing T‐cell zone, mantle zone, and germinal center.
At this stage, the mature B cells exit the bone marrow and enter the periphery. B cells mainly populate the lymphoid organs (spleen, lymph nodes, and mucosal lymphoid tissue) but they also migrate to other anatomical sites including the skin, respiratory and gastrointestinal tracks, and the blood. Within the periphery, contact with antigens that bind to the specific BCRs which they express activates B cells, causing them to proliferate and further differentiate resulting in (1) an expansion of the B cell clone and secretion of antibody, (2) generation of plasma cells that become a permanent source of secreted antibody, and (3) a population of long‐lived B memory cells poised to rapidly respond to future exposure to the same antigen. Collectively, this response is responsible for humoral immunity (Figure 2.9).
Antigen activation of B cells is a team effort due, in particular, to the need for T‐cell help (see Chapter 9) to optimally stimulate B cells. Most B‐cell responses to antigen are, therefore, T cell dependent. B‐cell activation also results in the generation of an even more diverse population of B cells due to a process called class switching in which the antibodies produced preserve their antigen specificity while displaying nonantigen‐binding regions that impart functional properties of the antibody molecules that differ from the original antibody (e.g., the ability to activate complement, an important component of the innate immune system; see Chapter 3). B‐cell activation also initiates a process called somatic hypermutation which allows B cells to express immunoglobulin molecules with altered affinity for the activating antigen – either higher or lower affinity than the starting population (see Chapter 9). This process is also known as affinity maturation.
Figure 2.6. Cells derived from common lymphoid progenitors (CLPs) include innate lymphoid cells (ILCs), B cells, NKT cells, and functionally distinct T cell subsets including cytotoxic T cells (TC), T cells that promote immunosuppression and tolerance (TReg) and a growing number of helper T cell (TH) populations. Illustrated here are TH cells called TH1, TH2, TH17, and TFH cells.
Figure 2.7. Antibody molecule showing transmembrane portion traversing the B cell plasma membrane. Antigen‐binding sites are present at the variable region composed of the amino‐terminal parts of two identical light (L) and two identical heavy (H) chains. Disulfide bonds bridge the L and H chains as well as the two H chains.
Source: © John Wiley & Sons, Inc.
Figure 2.8. B cell with BCR complex consisting of the four‐chain immunoglobulin polypeptide and the Igα/Igβ signaling molecules.
T Lymphocytes.
T lymphocytes (T cells), the mediators of cellular immunity, get their name from the organ site where the final maturation stages of bone marrow‐derived pre‐T cells take place, namely the thymus. Fully mature T cells emerge from the thymus as naïve T
