288 PART III Immune Effector Mechanisms Cytokine Secretion by TH1 Cytokine secretion and principal TABLE 12-4 functions of mouse THi and and TH2 Subsets TH2 subsets The immune response to a particular pathogen must induce Cytokine/function T an appropriate set of effector functions that can eliminate the disease agent or its toxic products from the host. For exam- CYTOKINE SECRETION ple, the neutralization of a soluble bacterial toxin requires L antibodies, whereas the response to an intracellular virus or to a bacterial cell requires cell-mediated cytotoxicity or TNF-P delayed-type hypersensitivity. a large body of evidence im- GM-CSF plicates differences in cytokine-secretion patterns among IL-3 TH-cell subsets as determinants of the type of immune onse made to a particular antigenic challenge D4 TH cells exert most of their helper functions l-10 through secreted cytokines, which either act on the cells that L13 produce them in an autocrine fashion or modulate the re- sponses of other cells through paracrine pathways. Although FUNCTIONS CD8* CTLs also secrete cytokines, their array of cytokines Help for total antibody production generally is more restricted than that of CD4 TH cells. As Help for igE production briefly discussed in Chapter 10, two CD4* TH-cell subpopu Help for IgG2a production lations designated THl and TH2, can be distinguished in vitro Eosinophil and mast-cell production by the cytokines they secrete. Both subsets secrete IL-3 and Macrophage activation GM-CSF but differ in the other cytokines they produce Delayed-type hypersensitivity Table 12-4). THl and TH2 cells are characterized by the fol- -cell activation lowing functional differences The THl subset is responsible for many cell-mediated SOURCE: Adapted from F Powrie and R L Coffman, 1993, Immunol. Today functions(e.g, delayed-type hypersensitivity and 14:270. activation of Tc cells)and for the production of opsonization-promoting IgG antibodies(i.e. antibodies that bind to the high-affinity Fc receptors of phagocytes and interact with the complement system). This subset is also associated with the promotion of excessive tion of fully cytotoxic Tc cells from CD8* precursors. This The TH2 subset stimulates eosinophil activation and pattern of cytokine production makes the THl subset partic- differentiation, provides help to B cells, and promotes ularly suited to respond to viral infections and intracellular the production of relatively large amounts of IgM, IgE, pathogens. Finally, IFN-y inhibits the expansion of the TH2 and noncomplement-activating IgG isotypes. The TH2 population. subset also supports allergic reactions The secretion of IL-4 and IL-5 by cells of the TH2 duces production of igE and supports eosinophil-mediated The differences in the cytokines secreted by THl and TH2 attack on helminth(roundworm) infections. IL-4 promotes a cells determine the different biological functions of these two pattern of class switching that produces Igg that does not subsets. a defining cytokine of the THl subset, IFN-Y, acti- activate the complement pathway(gGI in mice, for exam- vates macrophages, stimulating these cells to increase micro- ple). IL-4 also increases the extent to which B cells switch bicidal activity, up-regulate the level of class II MHC, and from igm to IgE. This effect on ige production meshes with crete cytokines such as IL-12, which induces TH cells to dif- eosinophil differentiation and activation by IL-5, because ferentiate into the THl subset IFN-y secretion by THl cells eosinophils are richly endowed with FcE receptors, which also induces antibody-class switching to IgG classes(such as bind IgE. Typically, roundworm infections induce TH2 IgG2a in the mouse)that support phagocytosis and fixation sponses and evoke anti- roundworm IgE antibody. The anti- of complement. TNF-B and IFN-y are cytokines that medi- body bound to the worm binds to the Fc receptors of ate inflammation, and it is their secretion that accounts for eosinophils, thus forming an antigen-specific bridge between the association of THl cells with inflammatory phenomena the worm and the eosinophils. The attack of the eosinophil such as delayed hypersensitivity( Chapter 16). THl cells pro- on the worm is triggered by crosslinking of the Fce-bound duce IL-2 and IFN-y cytokines that promote the differentia- IgE. Despite these beneficial actions of igE, it is also the IgCytokine Secretion by TH1 and TH2 Subsets The immune response to a particular pathogen must induce an appropriate set of effector functions that can eliminate the disease agent or its toxic products from the host. For exam￾ple, the neutralization of a soluble bacterial toxin requires antibodies, whereas the response to an intracellular virus or to a bacterial cell requires cell-mediated cytotoxicity or delayed-type hypersensitivity. A large body of evidence im￾plicates differences in cytokine-secretion patterns among TH-cell subsets as determinants of the type of immune response made to a particular antigenic challenge. CD4+ TH cells exert most of their helper functions through secreted cytokines, which either act on the cells that produce them in an autocrine fashion or modulate the re￾sponses of other cells through paracrine pathways. Although CD8+ CTLs also secrete cytokines, their array of cytokines generally is more restricted than that of CD4+ TH cells. As briefly discussed in Chapter 10, two CD4+ TH-cell subpopu￾lations designated TH1 and TH2, can be distinguished in vitro by the cytokines they secrete. Both subsets secrete IL-3 and GM-CSF but differ in the other cytokines they produce (Table 12-4). TH1 and TH2 cells are characterized by the fol￾lowing functional differences: ■ The TH1 subset is responsible for many cell-mediated functions (e.g., delayed-type hypersensitivity and activation of TC cells) and for the production of opsonization-promoting IgG antibodies (i.e. antibodies that bind to the high-affinity Fc receptors of phagocytes and interact with the complement system). This subset is also associated with the promotion of excessive inflammation and tissue injury. ■ The TH2 subset stimulates eosinophil activation and differentiation, provides help to B cells, and promotes the production of relatively large amounts of IgM, IgE, and noncomplement-activating IgG isotypes. The TH2 subset also supports allergic reactions. The differences in the cytokines secreted by TH1 and TH2 cells determine the different biological functions of these two subsets. A defining cytokine of the TH1 subset, IFN-, acti￾vates macrophages, stimulating these cells to increase micro￾bicidal activity, up-regulate the level of class II MHC, and secrete cytokines such as IL-12, which induces TH cells to dif￾ferentiate into the TH1 subset. IFN- secretion by TH1 cells also induces antibody-class switching to IgG classes (such as IgG2a in the mouse) that support phagocytosis and fixation of complement. TNF- and IFN- are cytokines that medi￾ate inflammation, and it is their secretion that accounts for the association of TH1 cells with inflammatory phenomena such as delayed hypersensitivity (Chapter 16). TH1 cells pro￾duce IL-2 and IFN- cytokines that promote the differentia￾tion of fully cytotoxic TC cells from CD8+ precursors. This pattern of cytokine production makes the TH1 subset partic￾ularly suited to respond to viral infections and intracellular pathogens. Finally, IFN- inhibits the expansion of the TH2 population. The secretion of IL-4 and IL-5 by cells of the TH2 subset in￾duces production of IgE and supports eosinophil-mediated attack on helminth (roundworm) infections. IL-4 promotes a pattern of class switching that produces IgG that does not activate the complement pathway (IgG1 in mice, for exam￾ple). IL-4 also increases the extent to which B cells switch from IgM to IgE. This effect on IgE production meshes with eosinophil differentiation and activation by IL-5, because eosinophils are richly endowed with Fc receptors, which bind IgE. Typically, roundworm infections induce TH2 re￾sponses and evoke anti-roundworm IgE antibody. The anti￾body bound to the worm binds to the Fc receptors of eosinophils, thus forming an antigen-specific bridge between the worm and the eosinophils. The attack of the eosinophil on the worm is triggered by crosslinking of the Fc-bound IgE. Despite these beneficial actions of IgE, it is also the Ig 288 PART III Immune Effector Mechanisms TABLE 12-4 Cytokine secretion and principal functions of mouse TH1 and TH2 subsets Cytokine/function TH1 TH2 CYTOKINE SECRETION IL-2 + – IFN- ++ – TNF- ++ – GM-CSF ++ + IL-3 ++ ++ IL-4 – ++ IL-5 – ++ IL-10 – ++ IL-13 – ++ FUNCTIONS Help for total antibody production + ++ Help for IgE production – ++ Help for IgG2a production ++ + Eosinophil and mast-cell production – ++ Macrophage activation ++ – Delayed-type hypersensitivity ++ – TC-cell activation ++ – SOURCE: Adapted from F. Powrie and R. L. Coffman, 1993, Immunol. Today 14:270.