Cristina M. Tato

Innate IL-17-producing cells: the sentinels of the immune system

The cytokine interleukin-17 (IL-17) has received considerable attention since the discovery of a distinct CD4+ T helper (TH) cell subset that produces it, known as the TH17 cell subset. Despite the fact that most of the recent literature describes IL-17 as a T cell-secreted cytokine, much of the IL-17 released during an inflammatory response is produced by innate immune cells. In this Review, we explore the many innate immune cell populations that are an early source of IL-17 in response to stress, injury or pathogens. These early sources have been shown to have a central role in the initiation of IL-17-dependent immune responses, even before the first CD4+T cell sees its cognate antigen and initiates the TH17 cell developmental programme.

Interleukin 27 negatively regulates the development of interleukin 17-producing T helper cells during chronic inflammation of the central nervous system.

Studies have focused on the events that influence the development of interleukin 17 (IL-17)–producing T helper cells (TH-17 cells) associated with autoimmunity, such as experimental autoimmune encephalitis, but relatively little is known about the cytokines that antagonize TH-17 cell effector responses. Here we show that IL-27 receptor–deficient mice chronically infected with Toxoplasma gondii developed severe neuroinflammation that was CD4+ T cell dependent and was associated with a prominent IL-17 response. In vitro, treatment of naive primary T cells with IL-27 suppressed the development TH-17 cells induced by IL-6 and transforming growth factor-β, which was dependent on the intracellular signaling molecule STAT1 but was independent of inhibition of IL-6 signaling mediated by the suppressor protein SOCS3. Thus IL-27, a potent inhibitor of TH-17 cell development, may be a useful target for treating inflammatory diseases mediated by these cells.

Generation of pathogenic T(H)17 cells in the absence of TGF-β signalling.

CD4+ T-helper cells that selectively produce interleukin (IL)-17 (TH17), are critical for host defence and autoimmunity. Although crucial for TH17 cells in vivo, IL-23 has been thought to be incapable of driving initial differentiation. Rather, IL-6 and transforming growth factor (TGF)-β1 have been proposed to be the factors responsible for initiating specification. Here we show that TH17 differentiation can occur in the absence of TGF-β signalling. Neither IL-6 nor IL-23 alone efficiently generated TH17 cells; however, these cytokines in combination with IL-1β effectively induced IL-17 production in naive precursors, independently of TGF-β. Epigenetic modification of the Il17a, Il17f and Rorc promoters proceeded without TGF-β1, allowing the generation of cells that co-expressed RORγt (encoded by Rorc) and T-bet. T-bet+RORγt+ TH17 cells are generated in vivo during experimental allergic encephalomyelitis, and adoptively transferred TH17 cells generated with IL-23 without TGF-β1 were pathogenic in this disease model. These data indicate an alternative mode for TH17 differentiation. Consistent with genetic data linking IL23R with autoimmunity, our findings re-emphasize the importance of IL-23 and therefore may have therapeutic implications.

The interleukin 23 receptor is essential for the terminal differentiation of interleukin 17-producing effector T helper cells in vivo.

Interleukin 23 (IL-23) is required for autoimmune inflammation mediated by IL-17-producing helper T cells (TH-17 cells) and has been linked to many human immune disorders. Here we restricted deficiency in the IL-23 receptor to defined cell populations in vivo to investigate the requirement for IL-23 signaling in the development and function of TH-17 cells in autoimmunity, inflammation and infection. In the absence of IL-23, TH-17 development was stalled at the early activation stage. TH-17 cells failed to downregulate IL-2 and also failed to maintain IL-17 production or upregulate expression of the IL-7 receptor α-chain. These defects were associated with less proliferation; consequently, fewer effector TH-17 cells were produced in the lymph nodes and hence available to emigrate to the bloodstream and tissues.

Lymphoid tissue inducer–like cells are an innate source of IL-17 and IL-22

The interleukin (IL) 17 family of cytokines has emerged to be critical for host defense as well as the pathogenesis of autoimmune and autoinflammatory disorders, and serves to link adaptive and innate responses. Recent studies have identified a new subset of T cells that selectively produce IL-17 (Th17 cells; Bettelli, E., T. Korn, and V.K. Kuchroo. 2007. Curr. Opin. Immunol. 19:652–657; Kolls, J.K., and A. Linden. 2004. Immunity. 21:467–476), but the regulation of IL-17 production by innate immune cells is less well understood. We report that in vitro stimulation with IL-23 induced IL-17 production by recombination activating gene (Rag) 2−/− splenocytes but not Rag2−/− common γ chain−/− splenocytes. We found that a major source of IL-17 was CD4+CD3−NK1.1−CD11b−Gr1−CD11c−B220− cells, a phenotype that corresponds to lymphoid tissue inducer–like cells (LTi-like cells), which constitutively expressed the IL-23 receptor, aryl hydrocarbon receptor, and CCR6. In vivo challenge with the yeast cell wall product zymosan rapidly induced IL-17 production in these cells. Genetic deletion of signal transducer and activator of transcription 3 reduced but did not abrogate IL-17 production in LTi-like cells. Thus, it appears that splenic LTi-like cells are a rapid source of IL-17 and IL-22, which might contribute to dynamic organization of secondary lymphoid organ structure or host defense.

IL-27 Blocks RORc Expression to Inhibit Lineage Commitment of Th17 Cells

IL-27 is secreted by APCs in response to inflammatory stimuli and exerts a proinflammatory Th1-enhancing activity but also has significant anti-inflammatory functions. We examined the molecular mechanism by which IL-27 regulates TGFβ plus IL-6- or IL-23-dependent Th17 development in the mouse and human systems. IL-27 inhibited the production of IL-17A and IL-17F in naive T cells by suppressing, in a STAT1-dependent manner, the expression of the Th17-specific transcription factor RORγt. The in vivo significance of the role of IL-27 was addressed in delayed-type hypersensitivity response and experimental autoimmune encephalomyelitis (EAE). By generating mice deficient for the p28 subunit of IL-27, we showed that IL-27 regulated the severity of delayed-type hypersensitivity response and EAE through its effects on Th17 cells. Furthermore, up-regulation of IL-10 in the CNS, which usually occurs late after EAE onset and plays a role in the resolution of the disease, was notably absent in IL-27p28−/− mice. These results show that IL-27 acts as a negative regulator of the developing IL-17A response in vivo, suggesting a potential therapeutic role for IL-27 in autoimmune diseases.

Interleukin-23-Independent IL-17 Production Regulates Intestinal Epithelial Permeability

Whether interleukin-17A (IL-17A) has pathogenic and/or protective roles in the gut mucosa is controversial and few studies have analyzed specific cell populations for protective functions within the inflamed colonic tissue. Here we have provided evidence for IL-17A-dependent regulation of the tight junction protein occludin during epithelial injury that limits excessive permeability and maintains barrier integrity. Analysis of epithelial cells showed that in the absence of signaling via the IL-17 receptor adaptor protein Act-1, the protective effect of IL-17A was abrogated and inflammation was enhanced. We have demonstrated that after acute intestinal injury, IL-23R(+) γδ T cells in the colonic lamina propria were the primary producers of early, gut-protective IL-17A, and this production of IL-17A was IL-23 independent, leaving protective IL-17 intact in the absence of IL-23. These results suggest that IL-17-producing γδ T cells are important for the maintenance and protection of epithelial barriers in the intestinal mucosa.

Immunology: what does it mean to be just 17?

For a long time it was thought that there are only two types of T helper cell. But it is becoming clear that there may be other lineages that influence inflammatory responses in certain circumstances.

Helper T cell IL-2 production is limited by negative feedback and STAT-dependent cytokine signals.

Although required for many fundamental immune processes, ranging from self-tolerance to pathogen immunity, interleukin (IL)-2 production is transient, and the mechanisms underlying this brevity remain unclear. These studies reveal that helper T cell IL-2 production is limited by a classic negative feedback loop that functions autonomously or in collaboration with other common γ chain (IL-4 and IL-7) and IL-6/IL-12 family cytokines (IL-12 and IL-27). Consistent with this model for cytokine-dependent regulation, they also demonstrate that the inhibitory effect can be mediated by several signal transducer and activator of transcription (STAT) family transcription factors, namely STAT5, STAT4, and STAT6. Collectively, these findings establish that IL-2 production is limited by a network of autocrine and paracrine signals that are readily available during acute inflammatory responses and, thus, provide a cellular and molecular basis for its transient pattern of expression.

Identification of a Role for NF-κB2 in the Regulation of Apoptosis and in Maintenance of T Cell-Mediated Immunity to Toxoplasma gondii

The NF-κB family of transcription factors are involved in the regulation of innate and adaptive immune functions associated with resistance to infection. To assess the role of NF-κB2 in the regulation of cell-mediated immunity, mice deficient in the NF-κB2 gene (NF-κB2−/−) were challenged with the intracellular parasite Toxoplasma gondii. Resistance to this opportunistic pathogen is dependent on the production of IL-12, which is required for the development of innate NK cell and adaptive T cell responses dominated by the production of IFN-γ necessary to control replication of this parasite. Although wild-type controls were resistant to T. gondii, NF-κB2−/− mice developed severe toxoplasmic encephalitis and succumbed to disease between 3 and 10 wk following infection. However, NF-κB2 was not required for the ability of macrophages to produce IL-12 or to inhibit parasite replication and during the acute stage of infection, NF-κB2−/− mice had no defect in their ability to produce IL-12 or IFN-γ and infection-induced NK cell responses appeared normal. In contrast, during the chronic phase of the infection, susceptibility of NF-κB2−/− mice to toxoplasmic encephalitis was associated with a reduced capacity of their splenocytes to produce IFN-γ associated with a loss of CD4+ and CD8+ T cells. This loss of T cells correlated with increased levels of apoptosis and with elevated expression of the pro-apoptotic molecule Fas by T cells from infected NF-κB2−/− mice. Together, these results suggest a role for NF-κB2 in the regulation of lymphocyte apoptosis and a unique role for this transcription factor in maintenance of T cell responses required for long-term resistance to T. gondii.