TFH cells, unlike the subsets described above, have not been produced efficiently in vitro, and so the requirements for their differentiation are not yet clearly established. IL-6 seems to be important for TFH development, but much remains to be learned about the control of this subset. One transcription factor important for TFH development is Bcl-6, which is required for the expression of CXCR5, the receptor for the chemokine CXCL13, which is produced by the stromal cells of the B-cell follicle. CXCR5 is essential for TFH localization in follicles, and is not expressed by other effector T-cell subsets. TFH cells also express ICOS, the ligand for which is expressed abundantly by B cells. ICOS seems crucial for the helper activity of TFH cells, because mice lacking ICOS show a severe defect in T-cell-dependent antibody responses. In addition to production of low amounts of cytokines characteristic of the effector T-cell subsets with which they develop in parallel (for example, IFN-γ, IL-4, or IL-17), and which promote different patterns of B-cell class switching, TFH cells produce high amounts of IL-21, a cytokine that supports the proliferation and differentiation of B cells into antibody-producing plasma cells.
9-22 CD4 T-cell subsets can cross-regulate each other’s differentiation through the cytokines they produce.
The various subsets of effector CD4 T cells each have very different functions. For the immune response to efficiently control different types of pathogens it must orchestrate a coordinated effector response that is dominated by one of these subsets. A principal means of achieving this is through the distinct ensemble of cytokines that are produced by the different subsets. Importantly, some of these same cytokines also participate in positive and negative feedback loops that control the differentiation of effector T cells from naive precursors, thereby providing a mechanism to promote one pattern of effector response while suppressing others. For example, both IFN-γ (produced by TH1 cells) and IL-4 (produced by TH2 cells) potently inhibit TH17 development, promoting TH1 or TH2 development, respectively (Fig. 9.34). Similarly, there is cross-regulation between TH1 and TH2 cells. IL-4 produced by TH2 cells potently inhibits TH1 development. Conversely, IFN-γ, a product of TH1 cells, can inhibit the proliferation of TH2 cells (see Fig. 9.34). TGF-β produced by T cells inhibits the development of both TH1 and TH2 cells. In this way, cytokines produced by effector T cells reinforce the differentiation of their own kind from naive precursor cells.
TH1 cells generate copious amounts of IFN-γ when they recognize antigen on a target cell, thus reinforcing the signal for the differentiation of more TH1 cells through a positive feedback loop. In this way, recognition of a particular type