As noted in Chapter 9, commitment of naive T cells to become TH17 cells is triggered by exposure to TGF-β and IL-6; commitment to become TH1 cells is initially triggered by IFN-γ. These initial conditions are not, however, sufficient to generate complete or effective TH17 or TH1 responses. In addition, each T-cell subset also requires stimulation by another cytokine: IL-23 in the case of TH17 cells, and IL-12 in the case of TH17 cells. IL-23 and IL-12 are closely related in structure; each is a heterodimer and they have a subunit in common (Fig. 11.17). IL-23 is composed of one p40 (IL-12 p40) and one p19 (IL-23 p19) subunit, whereas IL-12 has the p40 (IL-12 p40) subunit and a unique p35 (IL-12 p35) subunit. Committed TH17 cells express a receptor for IL-23, and, as will be discussed below, low levels of the receptor for IL-12. TH1 cells express the receptor for IL-12. The receptors for IL-12 and IL-23 are also related. They have a common subunit, IL-12Rβ1, which is expressed by naive T cells. Upon receipt of differentiating cytokine signals, developing TH17 cells synthesize IL-23R, the inducible component of the mature IL-23 receptor heterodimer;
TH1 cells from mice cured of infection with L. major are transferred into Rag2– or IL-12 p40–defcient mice, which are then injected with L. major
TH1 cells synthesize IL-12Rβ2, the inducible component of the mature IL-12 receptor.
IL-23 and IL-12 amplify the activities of TH17 and TH1 cells, respectively. Like many other cytokines, they both act through the JAK–STAT intracellular signaling pathway (see Fig. 9.32). IL-23 signaling primarily activates the intracellular transcriptional activator STAT3, but also activates STAT4. In contrast, IL-12 strongly activates STAT4, with minimal activation of STAT3. IL-23 does not initiate the commitment of naive CD4 T cells to become TH17 cells, but it does stimulate their expansion and contributes to their maintenance. Many in vivo responses that depend on IL-17 are diminished in the absence of IL-23. For example, mice lacking the IL-23-specific subunit p19 show decreased production of IL-17A and IL-17F in the lung after infection by Klebsiella pneumoniae.
IL-12 regulates the effector activity of committed TH1 cells at sites of infection. Studies of two different pathogens have shown that the initial differentiation of TH1 cells is not sufficient for protection, and that continuous signals are required. Mice deficient in IL-12 p40 can resist initial infection by Toxoplasma gondii as long as IL-12 is administered continuously. If IL-12 is administered during the first 2 weeks of infection, p40-deficient mice survive the initial infection and establish a latent chronic infection characterized by cysts containing the pathogen. When IL-12 administration is stopped, however, these mice gradually reactivate the latent cysts and the animals eventually die of toxoplasmic encephalitis. IFN-γ production by pathogen-specific T cells decreases in the absence of IL-12 but can be restored by IL-12 administration. Similarly, the adoptive transfer of differentiated TH1 cells from mice cured of Leishmania major protects RAG-deficient mice infected by L. major, but cannot protect IL-12 p40-deficient mice (Fig. 11.18). Together, these experiments indicate that TH1 cells continue to respond to signals during an infection, and that continuous IL-12 is needed to sustain the effectiveness of differentiated TH1 cells against at least some pathogens.