All the effector T cells described above are involved in activating their target cells to make responses that help clear pathogens from the body. Other CD4 T cells have a different function. These are called regulatory T cells, or Treg cells, because their function is to suppress T-cell responses rather than activate them. Thus, Treg cells are involved in limiting the immune response and preventing autoimmunity. Two main subsets of regulatory T cells are currently recognized. One subset becomes committed to a regulatory fate while still in the thymus, and is known as natural, or thymically derived, T cells (nT and tT , respectively; see Section 8-26). The other subset of T cells differenti ates from naive CD4 T cells in the periphery under the influence of particular environmental conditions. This group is known as induced, or peripherally derived, T cells (iT and pT , respectively). These cells will be discussed further in Section 9-23.
9-21 Cytokines induce the differentiation of naive CD4 T cells down distinct effector pathways.
Having briefly noted the types and functions of CD4 T-cell subsets, we will now consider how they are derived from naive T cells. The fate of the progeny of a naive CD4 T cell is largely defined during the initial priming period and is regulated by signals provided by the local environment, whether by the priming antigen-presenting cell or other innate immune cells that have been activated by a pathogen. As noted previously, the principal determinants of the developmental fate of naive CD4 T cells are the combination and balance of lineage-specifying cytokines, which are integrated with TCR and co-stimulatory signaling during priming. The five main subsets into which naive CD4 T cells may develop—TH1, TH2, TH17, TFH, and induced regulatory T cells (iTreg cells)—are associated with distinct signals that induce their formation, different transcription factors that drive their differentiation, and unique cytokines and surface markers that define their identity (Figs. 9.31 and 9.32).
TH1 development is induced when there is a predominance of the cytokines IFN-γand IL-12 during the early stages of naive T-cell activation. As described in Section 3-16, many key cytokines, including IFN-γ and IL-12, stimulate the JAK–STAT intracellular signaling pathway, resulting in the activation of specific gene networks. Different members of the JAK and STAT families are activated by different cytokines. Each of the effector pathways is dependent on a distinct pattern of STAT activation downstream of the lineage-specifying cytokines to program a unique transcription factor network that defines the gene-expression profile of mature effector T cells (see Fig. 9.32). For TH1 development, STAT1 and STAT4 are critical and are sequentially activated by interferons (type 1—IFN-α and IFN-β; or type 2—IFN-γ) and IL-12, respectively, which are produced by innate immune cells early during infection. Activated group 1 ILCs, such as NK cells, may also be an important source of IFN-γ. Finally, TH1 cells themselves may provide IFN-γ, thus reinforcing the signal for the differentiation of more TH1 cells through a positive feedback loop.
Fig. 9.31 Cytokines are the principal determinants of alternative programs of CD4 T-cell effector differentiation.