Cytokine 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 example, 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 implicates 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 responses 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 subpopulations 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 following 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-y, activates 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 differentiate into the TH1 subset. IFN-y 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-p and IFN-y are cytokines that mediate 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 produce IL-2 and IFN-y cytokines that promote the differentia-

Cytokine secretion and principal functions of mouse Th1 and Th2 subsets

Cytokine/function

Cytokine/function

CYTOKINE SECRETION

FUNCTIONS

Help for total antibody production + + +

Help for IgE production - ++

Help for IgG2a production ++ +

Eosinophil and mast-cell production - + +

Macrophage activation ++ -

Delayed-type hypersensitivity ++ -

SOURCE: Adapted from F. Powrie and R. L. Coffman, 1993, Immunol. Today 14:270.

tion of fully cytotoxic TC cells from CD8+ precursors. This pattern of cytokine production makes the TH1 subset particularly suited to respond to viral infections and intracellular pathogens. Finally, IFN-y inhibits the expansion of the TH2 population.

The secretion of IL-4 and IL-5 by cells of the TH2 subset induces 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 example). 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 Fce receptors, which bind IgE. Typically, roundworm infections induce TH2 responses and evoke anti-roundworm IgE antibody. The antibody 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 Fce-bound IgE. Despite these beneficial actions of IgE, it is also the Ig class responsible for allergy. Finally, IL-4 and IL-10 suppress the expansion of TH1 cell populations.

Because the TH1 and TH2 subsets were originally identified in long-term in vitro cultures of cloned T-cell lines, some researchers doubted that they represented true in vivo subpopulations. 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 during 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-7, 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 helminthic infections.

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  • Esa
    Which of the following cytokines is not secreted by th2 cells?
    1 year ago

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