Cytokines CHAPTER 12 289 class responsible for allergy. Finally, IL-4 and IL-10 suppress Positive feedback the expansion of THl cell populations Because the THl and TH2 subsets were originally identi fied in long-term in vitro cultures of cloned T-cell lines, some Ⅱ=(→IN5.Ⅱ2TNFB researchers doubted that they represented true in vivo sub Delayed-ty populations. They suggested instead that these subsets might hypersensitivity represent different maturational stages of a single lineage IL-2 Also, the initial failure to locate either subset in humans led k. Certain opsonic or some to believe that THl, TH2, and other subsets of T helper cells did not occur in this species. Further research corrected ii lg Gs these views. In many in vivo systems, the full commitment of populations of T cells to either the THl or TH2 phenotype MacrophageNaive often signals the endpoint of a chronic infection or allergy. or dendritic CD4+Tcell Hence it was difficult to find clear THl or TH2 subsets in studies employing healthy human subjects, who would not be at this stage of a response. Experiments with transgenic mice demonstrated conclusively that THl and TH2 cells arise independently. Furthermore, it was possible to demonstrate THl or TH2 populations in T cells isolated from humans dur ing chronic infectious disease or chronic episodes of allergy It is also important to emphasize that many helper T cells do not show either a THl ora TH2 profile; individual cells have shown striking heterogeneity in the TH-cell population. One FIGURE 12-12 Cytokine-mediated generation and cross regula of the best described of these is the THo subset which tion of TH subsets antigen-activated naive CD4* T cell produces lL-2 secretes IL-2, IL-4, IL-5, IFN-Y, and IL-10, as well as IL-3 and and proliferates. If it proliferates in an IL-12 dominated environment, GM-CSF Numerous reports of studies in both mice and humane it generates a population of TH1 cells that secretes a characteristic ofile of cytokines including interferon y A positive feedback loop is now document that the in vivo outcome of the immune established when IFN-y secreted by the expanding THI population response can be critically influenced by the relative levels of stimulates dendritic cells or macrophages to produce more IL-12. If THl-like or TH2-like activity. Typically, the THl profile of the environment is dominated by IL-4, a TH2 population emerges cytokines is higher in response to intracellular pathogens, and secretes a profile of cytokines that promotes eosinophil activa and the TH2 profile is higher in allergic diseases and hel- tion and the synthesis of certain antibody classes. Key cytokines pro- duced by each subset positively regulate the subset that produces it The Development of TH1 and TH2 Subsets and negatively regulate the other subset /Adapted from / Rengarajar S. Szabo, and L. Glimcher, 2000, Immunology Today 21: 479.1 Is Determined by the Cytokine Environment le 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-y, IL-12, and IL-18 all are impor tant in the physiology of the development of THl cells. The tion by both developing and fully differentiated THl cells source of IL-12, one of the key mediatiors of THl differentia- and by nK cells. So a regulatory network of cytokines posi- tion, is typically macrophages or dendritic cells activated tively controls the generation of THl cells. The critical role by an encounter with intracellular bacteria, with bacterial played by each of these cytokines and their receptors has products such as LPS, or with a number of other intracellular been demonstrated in a series of experiments in which either parasites. THl development is also critically dependent on the cytokine or its receptor has been knocked out Mice in IFN-Y, which induces a number of changes, including the which the genes for any of these critical components have up-regulation of IL-12 production by macrophages and den- been knocked out fail to generate populations of THl cells dritic cells, and the activation of the IL-12 receptor on acti- Just as THl cells require IL-12 and IFN-y, the generation vated T cells, which it accomplishes by up-regulating expres- of TH2 cells depends critically on IL-4 Exposing naive helper sion of the B chain of the IL-12 receptor. At the beginning of cells to IL-4 at the beginning of an immune response causes an immune response, IFN-y is generated by stimulation of them to differentiate into TH2 cells. In fact, this influence of T cells and can also come from activated NK cells. Yet another IL-4 is predominant in directing TH cells to the TH2 route cytokine, IL-18, promotes proliferation and IFN-y produc- Provided a threshold level of IL-4, TH2 development isclass responsible for allergy. Finally, IL-4 and IL-10 suppress the expansion of TH1 cell populations. Because the TH1 and TH2 subsets were originally identi￾fied in long-term in vitro cultures of cloned T-cell lines, some researchers doubted that they represented true in vivo sub￾populations. They suggested instead that these subsets might represent different maturational stages of a single lineage. Also, the initial failure to locate either subset in humans led some to believe that TH1, TH2, and other subsets of T helper cells did not occur in this species. Further research corrected these views. In many in vivo systems, the full commitment of populations of T cells to either the TH1 or TH2 phenotype often signals the endpoint of a chronic infection or allergy. Hence it was difficult to find clear TH1 or TH2 subsets in studies employing healthy human subjects, who would not be at this stage of a response. Experiments with transgenic mice demonstrated conclusively that TH1 and TH2 cells arise independently. Furthermore, it was possible to demonstrate TH1 or TH2 populations in T cells isolated from humans dur￾ing chronic infectious disease or chronic episodes of allergy. It is also important to emphasize that many helper T cells do not show either a TH1 or a TH2 profile; individual cells have shown striking heterogeneity in the TH-cell population. One of the best described of these is the TH0 subset, which secretes IL-2, IL-4, IL-5, IFN-, and IL-10, as well as IL-3 and GM-CSF. Numerous reports of studies in both mice and humans now document that the in vivo outcome of the immune response can be critically influenced by the relative levels of TH1-like or TH2-like activity. Typically, the TH1 profile of cytokines is higher in response to intracellular pathogens, and the TH2 profile is higher in allergic diseases and hel￾minthic infections. 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-, IL-12, and IL-18 all are impor￾tant in the physiology of the development of TH1 cells. The source of IL-12, one of the key mediatiors of TH1 differentia￾tion, 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-, which induces a number of changes, including the up-regulation of IL-12 production by macrophages and den￾dritic cells, and the activation of the IL-12 receptor on acti￾vated T cells, which it accomplishes by up-regulating expres￾sion of the chain of the IL-12 receptor. At the beginning of an immune response, IFN- is generated by stimulation of T cells and can also come from activated NK cells.Yet another cytokine, IL-18, promotes proliferation and IFN- produc￾tion by both developing and fully differentiated TH1 cells and by NK cells. So a regulatory network of cytokines posi￾tively 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-, 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 Cytokines CHAPTER 12 289 Macrophage or dendritic cell Positive feedback Positive feedback IL-2 Naive CD4+ T cell TH2 TH1 •Delayed-type hypersensitivity •Macrophage activation •Certain opsonic or complement-fixing IgGs IL-4 , IL-5, IL-10, IL-13 •Eosinophil activation •IgE and some other antibody classes IL-4 IL-12 IFN-δ , IL-2, TNF-β − − FIGURE 12-12 Cytokine-mediated generation and cross regula￾tion 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 . A positive feedback loop is established when IFN- 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 activa￾tion and the synthesis of certain antibody classes. Key cytokines pro￾duced by each subset positively regulate the subset that produces it and negatively regulate the other subset. [Adapted from J. Rengarajan, S. Szabo, and L. Glimcher, 2000, Immunology Today 21:479.]