Lymphocytes constantly travel between tissues and home to particular sites. Naive lymphocytes circulate through peripheral lymphoid organs where antigens are concentrated and immune responses are initiated, and effector lymphocytes migrate to sites of infection. The process of lymphocyte recirculation is most important for T cells, because naïve T cells have to “patrol” widely distributed peripheral lymphoid organs to find antigens, and effector T cells have to home to sites of infection to eliminate microbes. In contrast, plasma cells do not need to migrate to sites of infection because they secrete antibodies that are transported via the blood and lymph to distant tissues.
Cytokines: Messenger Molecules of the Immune System
Cytokines are secreted proteins that mediate immune and inflammatory reactions. Molecularly defined cytokines are called interleukins, a name implying a role in communication between leukocytes. Most cytokines have a wide spectrum of effects, and some are produced by several different cell types. The majority of these cytokines act on the cells that produce them or on neighboring cells, but some (like IL-1) have systemic effects.
Different cytokines contribute to specific types of immune responses.
In innate immune responses, cytokines are produced rapidly after microbes and other stimuli are encountered, and function to induce inflammation and inhibit virus replication. These cytokines include TNF, IL-1, IL-12, type I IFNs, IFN-γ, and chemokines (Chapter 3). Their major sources are macrophages, DCs, ILCs, and NK cells, but endothelial and epithelial cells also can produce them.
In adaptive immune responses, cytokines are produced principally by CD4+ T lymphocytes activated by antigen and other signals, and function to promote lymphocyte proliferation and differentiation and to activate effector cells. The main ones in this group are IL-2, IL-4, IL-5, IL-17, and IFN-γ; their roles in immune responses are described later. Some cytokines serve mainly to limit and terminate immune responses; these include TGF-β and IL-10.
• Some cytokines stimulate hematopoiesis and are called colony-stimulating factors because they stimulate formation of blood cell colonies from bone marrow progenitors (Chapter 12). Their functions are to increase leukocyte numbers during immune and inflammatory responses, and to replace leukocytes that are consumed during such responses. They are produced by marrow stromal cells, T lymphocytes, macrophages, and other cells. Examples include GM-CSF and IL-7.
The knowledge gained about cytokines has numerous practical therapeutic applications. Inhibiting cytokine production or actions can control the harmful effects of inflammation and tissue-damaging immune reactions. Patients with rheumatoid arthritis often show dramatic responses to TNF antagonists, an elegant example of rationally designed and molecularly targeted therapy. Many other cytokine antagonists are now approved for the treatment of various inflammatory disorders. Conversely, administration of cytokines is used to boost reactions that are normally dependent on these proteins, such as hematopoiesis and defense against some viruses.
Adaptive immune responses develop in steps, consisting of: antigen recognition; activation, proliferation and differentiation of specific lymphocytes into effector and memory cells; elimination of the antigen; and decline of the response, with memory cells being the long-lived survivors. The major events in each step are summarized next; these general principles apply to protective responses against microbes as well as pathologic responses that injure the host.
Microbes and other foreign antigens can enter the body virtually anywhere, and it is obviously impossible for lymphocytes of every specificity to patrol every possible portal of antigen entry. To overcome this problem, microbes and their protein antigens in epithelia and other tissues are captured by resident dendritic cells, which then carry their antigenic cargo to draining lymph nodes through which T cells constantly recirculate (