So far we have focused on how the innate immune system recognizes microbes and combats infections. We mentioned at the beginning of this chapter that, in addition to its roles in host defense, the innate immune response to microbes serves an important warning function by alerting the adaptive immune system that an effective immune response is needed. In this final section, we summarize some of the mechanisms by which innate immune responses stimulate adaptive immune responses.

Innate immune responses generate molecules that provide signals, in addition to antigens, that are required to activate naive T and B lymphocytes.

Antigen may be referred to as signal 1, and innate immune responses to microbes and to host cells damaged by microbes may provide signal 2 (Fig. 1). The stimuli that warn the adaptive immune system that it needs to respond have also been called danger signals. This requirement for microbe-dependent second signals ensures that lymphocytes respond to infectious agents and not to harmless, noninfectious substances. In experimental situations or for vaccination, adaptive immune responses may be induced by antigens without microbes. In all such instances, the antigens need to be administered with substances called adjuvants that elicit the same innate immune reactions as microbes do. In fact, many potent adjuvants are the products of microbes. Here we describe two illustrative examples of second signals that are generated during innate immune reactions.

fig1. Two-signal requirement for lymphocyte activation. Antigen recognition by lymphocytes provides signal 1 for activation of the lymphocytes, and substances produced during innate immune responses to microbes (or components of microbes) provide signal 2. In this illustration, the lymphocytes could be T cells or B cells. By convention, the major second signals for T cells are called costimulators because they function together with antigens to stimulate the cells.

In infected tissues, microbes (or IFN-γ produced by NK cells in response to microbes) stimulate dendritic cells and macrophages to produce two types of second signals that can activate T lymphocytes. First, dendritic cells increase their expression of surface molecules called costimulators, which bind to receptors on naive T cells and function together with antigen recognition to activate the T cells. Second, the dendritic cells and macrophages secrete cytokines such as IL-12, IL-1, and IL-6, which stimulate the differentiation of naive T cells into effector cells of cell-mediated adaptive immunity.

Blood-borne microbes activate the complement system by the alternative pathway. One of the proteins produced during complement activation by proteolysis of C3b, called C3d, becomes covalently attached to the microbe. At the same time that B lymphocytes recognize microbial antigens by their antigen receptors, the B cells recognize the C3d bound to the microbe by a receptor for C3d. The combination of antigen recognition and C3d recognition initiates the process of B cell differentiation into antibody-secreting cells. Thus, a complement product serves as the second signal for humoral immune responses.

These examples illustrate an important feature of second signals: these signals not only stimulate adaptive immunity, but they also guide the nature of the adaptive immune response. Intracellular and phagocytosed microbes need to be eliminated by cell-mediated immunity, the adaptive response mediated by T lymphocytes. Microbes that are encountered and ingested by dendritic cells or macrophages induce the second signals— that is, costimulators and cytokines—that stimulate T cell responses. By contrast, blood-borne microbes need to be combated by antibodies, which are produced by B lymphocytes during humoral immune responses. Blood-borne microbes activate the plasma complement system, which in turn stimulates B cell activation and antibody production. Thus, different types of microbes induce innate immune responses that stimulate the types of adaptive immunity that are best able to combat different infectious pathogens.