The Development of TH1 and TH2 Subsets Is Determined by the Cytokine Environment

The cytokine environment in which antigen-primed TH cells differentiate determines the subset that develops (Figure 12-12). In particular, IL-4 is essential for the development of a Th2 response, and IFN-7, IL-12, and IL-18 all are important in the physiology of the development of TH1 cells. The source of IL-12, one of the key mediatiors of TH1 differentiation, is typically macrophages or dendritic cells activated by an encounter with intracellular bacteria, with bacterial products such as LPS, or with a number of other intracellular parasites. TH1 development is also critically dependent on IFN-7, which induces a number of changes, including the up-regulation of IL-12 production by macrophages and dendritic cells, and the activation of the IL-12 receptor on activated T cells, which it accomplishes by up-regulating expression of the p chain of the IL-12 receptor. At the beginning of an immune response, IFN-7 is generated by stimulation of T cells and can also come from activated NK cells. Yet another cytokine, IL-18, promotes proliferation and IFN-7 produc-

Positive feedback

Macrophage Naive or dendritic CD4+ T cell cell

• Delayed-type hypersensitivity

• Macrophage activation

• Certain opsonic or complement-fixing IgGs

• Delayed-type hypersensitivity

• Macrophage activation

• Certain opsonic or complement-fixing IgGs

• Eosinophil activation

• IgE and some other antibody classes

Positive feedback

FIGURE 12-12

Cytokine-mediated generation and cross regulation of Th subsets. Antigen-activated naive CD4+ T cell produces IL-2 and proliferates. If it proliferates in an IL-12 dominated environment, it generates a population of TH1 cells that secretes a characteristic profile of cytokines including interferon 7. A positive feedback loop is established when IFN-7 secreted by the expanding TH1 population stimulates dendritic cells or macrophages to produce more IL-12. If the environment is dominated by IL-4, a TH2 population emerges and secretes a profile of cytokines that promotes eosinophil activation and the synthesis of certain antibody classes. Key cytokines produced by each subset positively regulate the subset that produces it and negatively regulate the other subset. [Adapted from J. Rengarajan, S. Szabo, andL. Glimcher, 2000, Immunology Today 21:479.]

tion by both developing and fully differentiated TH1 cells and by NK cells. So a regulatory network of cytokines positively controls the generation of TH1 cells. The critical role played by each of these cytokines and their receptors has been demonstrated in a series of experiments in which either the cytokine or its receptor has been knocked out. Mice in which the genes for any of these critical components have been knocked out fail to generate populations of TH1 cells.

Just as Th1 cells require IL-12 and IFN-7, the generation of Th2 cells depends critically on IL-4. Exposing naive helper cells to IL-4 at the beginning of an immune response causes them to differentiate into TH2 cells. In fact, this influence of IL-4 is predominant in directing TH cells to the TH2 route. Provided a threshold level of IL-4, TH2 development is greatly favored over TH1 even if IL-12 is present. The critical role of signals from IL-4 in TH2 development is shown by the observation that knocking out the gene that encodes IL-4 prevents the development of this T-cell subset. Additional evidence supporting the central role of IL-4 comes from an experiment that interrupted the IL-4 signal-transduction pathway. Like so many other cytokines, IL-4 uses a pathway that involves JAK and STAT proteins. The Stat6 transcription factor is the one activated in signaling by IL-4. Consequently, in mice in which the gene for Stat6 has been disrupted (Stat6 knockouts), IL-4 mediated processes are severely inhibited or absent. The observation that Stat6 knockout mice have very few Th2 cells confirms the importance of IL-4 for the differentiation of this subset.

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