Stimulation Of Adaptive Immunity

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The innate immune response provides signals that function in concert with antigen to stimulate the proliferation and differentiation of antigen-specific T and B lymphocytes. As the innate immune response is providing the initial defense against microbes, it also sets in motion the adaptive immune response. The activation of lymphocytes requires two distinct signals, the first being antigen and the second being molecules that are produced during innate immune responses to microbes or injured cells (Fig. 4-16). This idea is called the two-signal hypothesis for lymphocyte activation. The requirement for antigen (so-called signal 1) ensures that the ensuing immune response is specific. The requirement for additional stimuli triggered by innate immune reactions to microbes (signal 2) ensures that adaptive immune responses are induced when there is a dangerous infection and not when lymphocytes recognize harmless antigens, including self antigens. The molecules produced during innate immune reactions that function as second signals for lymphocyte activation include costimulators (for T cells), cytokines (for both T and B cells), and complement breakdown products (for B cells). We will

Lymphocyte

Antigen receptor

Microbial antigen

Lymphocyte

Antigen receptor

Microbial antigen

Molecule induced by innate response (e.g., costimulator, complement fragment)

FIGURE 4-16 Stimulation of adaptive immunity by innate immune responses. Antigen recognition by lymphocytes provides signal 1 for the activation of the lymphocytes, and molecules induced on host cells during innate immune responses to microbes provide signal 2. In this illustration, the lymphocytes are B cells, but the same principles apply to T lymphocytes. The nature of second signals differs for B and T cells and is described in later chapters.

FIGURE 4-16 Stimulation of adaptive immunity by innate immune responses. Antigen recognition by lymphocytes provides signal 1 for the activation of the lymphocytes, and molecules induced on host cells during innate immune responses to microbes provide signal 2. In this illustration, the lymphocytes are B cells, but the same principles apply to T lymphocytes. The nature of second signals differs for B and T cells and is described in later chapters.

return to the nature of second signals for lymphocyte activation in Chapters 9 and 11.

The second signals generated during innate immune responses to different microbes not only enhance the magnitude of the subsequent adaptive immune response but also influence the nature of the adaptive response. A major function of T cell-mediated immunity is to activate macrophages to kill intracellular microbes and to induce robust acute inflammatory responses, beyond those directly induced by the innate immune system, so that a sufficiently large army of phagocytes is called into a site of infection. Infectious agents that engage TLRs and other pattern recognition receptors will tend to stimulate T cell-mediated immune responses. This is because the signaling from these pattern recognition receptors enhances the ability of antigen-presenting cells to induce the differentiation of naive CD4+ T cells into effector cells called Th1 and TH17 cells. TH1 cells produce the cytokine IFN-y, which can activate macrophages to kill microbes that might otherwise survive within phagocytic vesicles. Th17 cells produce the cytokine IL-17, which can induce neutrophil-rich inflammation. TH1 and TH17 cellmediated immunity is discussed in detail in Chapters 9 and 10. Many extracellular microbes that enter the blood activate the alternative complement pathway, which in turn enhances the production of antibodies by B lymphocytes. Some of these antibodies opsonize the bacteria and thereby promote their phagocytosis by neutrophils and macrophages. Therefore, humoral immune response serves to eliminate extracellular microbes. The role of complement in enhancing B cell activation is discussed in Chapter 11.

Cytokines produced by cells during innate immune responses to microbes stimulate the proliferation and differentiation of lymphocytes in adaptive immune responses. Examples of cytokines secreted by PAMP-stimulated cells acting on B cells, CD4+ T cells, and CD8+ T cells are given here. The details of the lymphocyte responses to these cytokines will be discussed in more detail in later chapters.

• IL-6 promotes the production of antibodies by activated B cells (see Chapter 11).

• IL-1, IL-6, and IL-23 stimulate the differentiation of naive CD4+ T cells to the TH17 subset of effector cells (see Chapter 9).

• IL-12 stimulates the differentiation of naive CD4+ T cells to the TH1 subset of effector cells (see Chapter 9).

• IL-15 promotes the survival of memory CD8+ T cells.

Adjuvants, which are substances that need to be administered together with purified protein antigens to elicit maximal T cell-dependent immune responses (see Chapter 6), work by stimulating innate immune responses at the site of antigen exposure. Adjuvants are useful in experimental immunology and in clinical vaccines. Many adjuvants in experimental use are microbial products, such as killed mycobacteria and LPS, that engage TLRs. The only routinely used adjuvant in human vaccines is alum, composed of either aluminum hydroxide or aluminum phosphate. Among their important effects, adjuvants activate dendritic cells to express more major histocompatibility molecules that are part of the antigen (signal 1) that T cells recognize, increase the expression of costimulators (signal 2) and cytokines needed for T cell activation, and stimulate migration of the dendritic cells to lymph nodes where T cells are located.

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