Cytokine Profiles Are Cross Regulated

The critical cytokines produced by TH1 and TH2 subsets have two characteristic effects on subset development. First, they promote the growth of the subset that produces them; second, they inhibit the development and activity of the opposite subset, an effect known as cross-regulation, (see Figure 12-12). For instance, IFN-7 (secreted by the TH1 subset) preferentially inhibits proliferation of the TH2 subset, and IL-4 and IL-10 (secreted by the TH2 subset) down-regulate secretion of IL-12, one of the critical cytokines for TH1 differentiation, by both macrophages and dendritic cells. Similarly, these cytokines have opposing effects on target cells other than TH subsets. IFN-7 secreted by the TH1 subset promotes IgG2a production by B cells but inhibits IgG1 and IgE production. On the other hand, IL-4 secreted by the TH2 subset promotes production of IgG1 and IgE and suppresses production of IgG2a. The phenomenon of cross-regulation explains the observation that there is often an inverse relationship between antibody production and cell-mediated immunity; that is, when antibody production is high, cellmediated immunity is low, and vice versa. Furthermore, recent research has shown that IL-4 and IFN-7 make members of the T-cell subset that releases them less responsive to the cytokine that directs differentiation of the other T-cell subset. Thus, IL-4 enhances TH2 cell development by making TH cells less susceptible to the cytokine signals that cause these cells to enter a differentiation pathway that would lead to TH1 development. On the other hand, as explained below, IFN-7 up-regulates the expression of a key regulatory molecule that favors the differentiation and activity of TH1 cells.

Recent work has given insight into the molecular basis for the cytokine-mediated cross-regulation by which one subset promotes its own expansion and development while inhibiting the development of the opposite subset. Two transcription factors, T-Bet and GATA-3, are key elements in determining subset commitment and cross-regulation. The expression of T-Bet drives cells to differentiate into TH1 cells and suppresses their differentiation along the TH2 pathway. Expression of GATA-3 does the opposite, promoting the de velopment of naive T cells into TH2 cells while suppressing their differentiation into TH1 cells. As shown in Figure 12-13, the expression of T-Bet versus GATA-3 is determined by the cytokines IFN-7 and IL-4. In the presence of IFN-7, T cells up-regulate the expression of T-Bet and down-regulate GATA-3. This IFN-7 receptor/Stat1-dependent process shifts the cytokine profile to the production of IFN-7, the signature cytokine of Th1 cells, and other cytokines typical of the TH1 set. On the other hand, in a process that involves the IL-4 receptor and Stat6, IL-4 induces the cell to produce IL-4 and other TH2 cytokines. Further study has revealed that the up-regulation of T-Bet represses the expression of GATA-3. Similarly, expression of GATA-3 down-regulates T-Bet. Consequently, cytokine signals that induce one of these transcription factors set in motion a chain of events that repress the other. At the intracellular level, the differentiation of a T cell along the Th1 pathway, prevents its development of TH2 characteristics and vice versa.

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IL-4

IL-4

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FIGURE 12-13

Cross-regulation at the intracellular level. Signals through the TCR and cytokine receptors determine whether the cell will produce the TH1 -promoting transcription factor, T-Bet, or the TH2-promoting transcription factor, GATA-3. Experimental evidence supports a model in which exposure of cells bearing receptors for IFN-7 to IFN-7 induces the formation of T-Bet, which up-regulates the synthesis of IFN-7 and represses the expression of GATA-3. Exposure of IL-4 R-bearing cells to IL-4 induces the formation of GATA-3, which up-regulates the synthesis of IL-4 and IL-5 but represses the expression of T-Bet. [Adapted from J. Rengarajan, S. Szabo, and L. Glimcher, 2000, Immunology Today 21:479.]

Th1 activity Th2 activity

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The cross-regulation of TH1 cells by IL-10 secreted from TH2 cells is not a direct inhibition of the TH1 cells; instead, IL-10 acts on monocytes and macrophages, interfering with their ability to activate the TH1 subset. This interference is thought to result from the demonstrated ability of IL-10 to down-regulate the expression of class II MHC molecules on these antigen-presenting cells. IL-10 has other potent immu-nosuppressant effects on the monocyte-macrophage lineage, such as suppressing the production of nitric oxide and other bactericidal metabolites involved in the destruction of pathogens, and also suppressing the production of various inflammatory mediators (e.g., IL-1, IL-6, IL-8, GM-CSF, G-CSF, and TNF-7). These suppressive effects on the macrophage serve to further diminish the biologic consequences of TH1 activation.

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