of the epitope-MHC II with the CD4-TCR and CD3 complexes and signal 2 occurs upon costimulation through the CD28 binding to CD80 or CD86 on the APC.
Antigen presentation and binding to the TCR stimulates the T cell to become either a CTL or a T helper (Th) cell (Figure 4-9). Display of intracellularly derived peptide epitopes on MHC I allows the APC to activate and stimulate the proliferation of CTLs. CTLs are distinguished by the presence of CD8 molecules on their surfaces (hence the name CD8+ cytotoxic T cells). The CD8 molecules, along with the T cell receptor (TCR), are responsible for recognizing only antigen-bound MHC I complexes on the APC. CD8 binds to MHC I and stabilizes the interaction between epitope-bound MHC I and the TCR. CTLs are particularly well equipped to recognize infected cells because virtually all cells of the body produce MHC I. If a cell is infected, it displays epitopes from the invading microbe on its surface. Binding of a CTL to the surface of an infected cell causes the CTL to release cytolytic or apoptotic proteins that can kill the infected cell, as described earlier (see Figure 4-5). In addition, as described in chapter 3, NK cells also use the amount of MHC I on cell surfaces as an indicator of cell health, because infected cells generally express less MHC I than normal cells.
Figure 4-9. T-cell-mediated immunity and memory. Characteristics of the antigen (Ag) determine whether the antigen is presented via APCs through MHC I complexes or through MHC II complexes. Ag-MHCI complexes bind to TCRs on CD8+ T cells that trigger the CTL response. Ag-MHC II complexes that bind to TCRs on CD4+ Th0 cells trigger IL-2 cytokine production and maturation into CD4+ Th1 cells, leading to cellular immunity or, in the subsequent presence of IL-4 into CD4+ Th2 cells, leading to stimulation of the antibody-producing B cell response. Cytokines and the presence of Th17 cells help direct the type of cell-mediated immunity and memory that occurs. Treg cells help control the immune response, especially once the pathogen has been cleared from the system.
In contrast, if an epitope is presented by the APC in complex with MHC II rather than MHC I, a different class of T cells, T helper (Th) cells, is stimulated. Complex formation between TCRs and coreceptor CD4 molecules on the surface of precursor Th cells (called CD4+ Th0 cells) with epitope-bound MHC II molecules on the surface of APCs leads to production of IL-2 and then IL-4 by the Th0 cell and proliferation and maturation. Proliferating Th cells come in two types: Th1 and Th2 cells. These Th cells influence a variety of immune responses through release of cytokines, and how they do this is a very active area of research in the field of immunology.
Other proteins on the surface of the APC and the Th cell, called costimulatory molecules (e.g., CD54, CD11a/CD18, CD58, CD2), must also interact to make the binding between the APC and the Th cell tight enough to stimulate the APC to release cytokines that stimulate the Th cell to proliferate and become activated. Th1 cells are stimulated to proliferate by IL-12 and IL-2 released by APCs, which causes the Th1 cells to release more IL-2 (positive feedback), IFN-γ, and TGF-β. Recognition of MHC II-epitope by CD4+ Th1 cells also stimulates the production and release of IL-2 and IFN-γ, which in turn activate macrophages. Th1-cell-mediated responses lead to cellular immunity, which is most effective against intracellular pathogens. The necessity for contacts between different surface proteins of the APC and the Th cell helps ensure that only specific binding of an MHC-epitope complex to its cognate TCR will result in Th cell activation.
Th2 cells are stimulated to proliferate by IL-4, which causes the cells to release more IL-4 (positive feedback), as well as other cytokines (IL-5, IL-9, IL-10, and IL-13), which modulate other immune cells. MHC II-epitope stimulation of CD4+ Th2 cells stimulates naïve B cells to proliferate into B cells and mature into antibody-producing plasma cells (i.e., humoral immunity) and memory B cells. IL-4 also stimulates B cells to produce IgE antibodies, which in turn stimulate mast cells to release their cytokines (histamine, serotonin, and leukotrienes). The Th2 response is most effective against extracellular pathogens.
Once activated, T cells begin to proliferate, with most of the resulting effector Th cells becoming involved in combating the invading microbes. A few of the T cells, however, become quiescent memory T cells. Memory T cells persist for long periods in the body. They are generally present in higher numbers than naïve T cells with the same TCR, and they are more easily stimulated to proliferate and produce stronger cytokine responses when they encounter their specific epitopes on APCs during subsequent infections. Memory T cells thus allow the body to respond to a second encounter with a particular microbial invader much faster and more strongly than it did after the initial encounter.
Some bacteria and viruses produce proteins called superantigens that interfere with this highly specific progression of events in an interesting way that will be described in greater detail in chapter 12. Superantigens force a close association between APCs and T cells through abnormal association of MHC and the TCRs without a matched antigen. Normally, only a small fraction of T cells will interact with APCs presenting antigens on their surface. Superantigens, on the other hand, can cause up to 20% of T cells to participate in such interactions. As the cytokine signaling begins, cytokines are produced at higher levels than normal and this overreaction can trigger shock. The term “septic shock” is sometimes used to describe this phenomenon; however, as described in chapter 3, LPS or other bacterial surface components usually initiate what is considered septic shock. The term “T-cell-mediated shock” or “toxic shock” might be more appropriate to describe the shock initiated by superantigens, to distinguish it from septic shock.
Th-(Th1/Th2/Th17)-Cell-Mediated Immunity
A paradigm for the process by which T helper (Th) cells influence the development of different types of immunity (such as cytotoxic T cells, activated macrophages, antibodies, and the IgE response) has emerged in recent years. The simplest form of this paradigm is the Th1/Th2 cell model, in which there are two subtypes, Th1 and Th2, that control the development of acquired immunity (Figure 4-9). Both Th1 and Th2 cells are descended from the same cell type, Th0. The decision to produce Th1 cells is triggered in part by PMN production of IL-12, which stimulates NK cells to produce IFN-γ, which in turn stimulates Th0 cells to differentiate into the Th1 form. Extracellular antigens stimulate differentiation of Th0 cells to develop into Th2 cells. IL-4 is required for Th2 differentiation and is later produced by mature Th2 cells. Cytokines produced by Th1 cells, such as IFN-γ, or by Th2 cells, such as IL-4, induce a positive feedback loop that leads to further differentiation of Th0 cells into Th1 or Th2 cells, respectively, and inhibits production of the other cell type. Later in the course of combating infection, the balance between Th1 and Th2 differentiation is eventually restored.
A third, more recently discovered pathway is the Th17 pathway (Figure 4-9), so called because Th17 cells are CD4+ Th cells and CD8+ cytotoxic T cells that produce IL-17. The main protective role of the Th17 pathway is thought to stimulate proinflammatory reactions that lead to recruitment of PMNs and neutrophils in tissues. Th17 cells also produce other cytokines, including IL-22, which induces antimicrobial peptide production by epithelial cells that protect against extracellular bacteria and fungi.
Th2 cells activate eosinophils and stimulate B cells to produce antibodies of the IgG1 class (the most effective opsonizing antibodies) as well as antibodies of the IgE class (the class associated with the allergic or antimetazoan response). Th2 cells also produce IL-10 and IL-13, cytokines that downregulate some cells of the immune system. Thus, the Th1-type response is the most desirable type of response to viral and intracellular bacterial infections. The Th2-type response produces the more effective opsonizing antibodies, which are important for clearing extracellular bacterial pathogens. An example of the type of Th1 or Th2 response that is elicited and its importance in disease outcome is illustrated in Box 4-3.