Immunology. Richard Coico
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 cells. All T cells express T cell receptors (TCR) in association with CD3, which, together with other transmembrane signal transduction molecules (ζ homodimers), enable cells to communicate with the nucleus when the T cell binds to its specific antigen (Figure 2.10). T‐cell activation and signaling mechanisms are discussed in detail in Chapter 10.
As shown in Figure 2.6, T cells differentiate from common lymphoid progenitor cells into a variety of functionally distinct T‐cell subsets. As noted earlier, the bone marrow environment where T cells first develop is not equipped to promote the final maturation stages of T cells. That process takes place within the thymus.
Phenotypically, fully mature T cells, all of which express the cluster of differentiation (CD) molecule CD3 (see Figure 2.10), can be broadly divided into cells expressing CD4 or CD8. Cytotoxic T cells (TC) capable of killing target cells expressing antigens recognized by their TCRs express both CD3 and CD8 on their membranes whereas all other T‐cell subsets express CD3 and CD4. The CD4 cells are further subdivided into the different subsets shown in Figure 2.10 including TH1, TH2, TH17, and TFollicular Helper (TFH) cells. As discussed below, each of these subsets has characteristic functional properties mainly due to their associated cytokine and transcription factor profiles.
Figure 2.9. T‐cell‐dependent antigen activation of B cells. The antigen stimulates a member of a B‐cell clone expressing a BCR with antigen specificity. Activation requires TH cell help which provides proliferation and differentiation factors (cytokines) to facilitate B cell proliferation and differentiation into antibody‐secreting plasma cells and memory cells.
Naïve Lymphocytes.
Our understanding of how T cells further differentiate into various subsets with characteristic functional properties has recently expanded significantly. Nevertheless, there is still much to be learned regarding the regulatory mechanisms controlling the destiny of naïve T cells which have not yet interacted with antigens in the periphery.
The T‐cell repertoire is first shaped by thymic selection (positive and negative; see Chapter 10). Naïve, fully mature CD4+ and CD8+ T cells emerging from the thymus are poised to interact, and be activated by antigens for which their TCRs are specific. They typically live for 1–3 months and their survival requires signals from antigen receptors and cytokines, particularly IL‐7. Naïve T cells recirculate from blood through a lymph node and back to blood every 12–24 hours. It is estimated that about 1 in 100,000 naïve T cells is likely to respond to any given antigen. Hence, this rapid recirculation increases the chances that a T cell will encounter the antigen recognized by its TCR. Table 2.1 summarizes the major properties of naïve CD4+and CD8+ cells.
CTL Effector Cells.
When naïve CD8+ cells encounter antigen‐presenting cells expressing antigenic peptides that bind to their TCR, they are activated and differentiate into cytotoxic killer cells (CTL). Activation also induces the generation of long‐lived memory CTLs to equip the host with sustainable immunity to the antigenic stimulus (e.g., viruses and other intracellular pathogens). Phenotpically, CTLs express αβ TCR, CD3, and CD8 and produce signature cytokines that include IL‐2 and interferon (IFN)‐γ. Their most distinguishing property is the presence of cytoplasmic granules filled with proteins including perforin and granzymes that, when released upon CTL–target cell interaction, kill the target cells. Target cells susceptible to CTL killing include virus‐infected cells and tumor cells (Figure 2.11).
Subsets of TH Cells.
T cell antigen engagement in secondary lymphoid tissues shapes the repertoire of antigen‐specific T cells and defines their functional attributes. In other words, antigen engagement directs the responding T cell towards a specific functional subset which include TH1, TH2, TH17, TFH, and TReg cells. Note that other