Craig L. Maynard

Late Developmental Plasticity in the T Helper 17 Lineage

Development of T helper (Th) 17 cells requires transforming growth factor (TGF)-beta and interleukin (IL)-6 and is independent of the Th1 pathway. Although T cells that produce interferon (IFN)-gamma are a recognized feature of Th17 cell responses, mice deficient for STAT4 and T-bet-two prototypical Th1 transcription factors-are protected from autoimmunity associated with Th17 pathogenesis. To examine the fate and pathogenic potential of Th17 cells and origin of IFN-gamma-producing T cells that emerge during Th17 immunity, we developed IL-17F reporter mice that identify cells committed to expression of IL-17F and IL-17A. Th17 cells required TGF-beta for sustained expression of IL-17F and IL-17A. In the absence of TGF-beta, both IL-23 and IL-12 acted to suppress IL-17 and enhance IFN-gamma production in a STAT4- and T-bet-dependent manner, albeit with distinct efficiencies. These results support a model of late Th17 developmental plasticity with implications for autoimmunity and host defense.

Reciprocal interactions of the intestinal microbiota and immune system

The emergence of the adaptive immune system in vertebrates set the stage for evolution of an advanced symbiotic relationship with the intestinal microbiota. The defining features of specificity and memory that characterize adaptive immunity have afforded vertebrates the mechanisms for efficiently tailoring immune responses to diverse types of microbes, whether to promote mutualism or host defence. These same attributes can put the host at risk of immune-mediated diseases that are increasingly linked to the intestinal microbiota. Understanding how the adaptive immune system copes with the remarkable number and diversity of microbes that colonize the digestive tract, and how the system integrates with more primitive innate immune mechanisms to maintain immune homeostasis, holds considerable promise for new approaches to modulate immune networks to treat and prevent disease.

Acute Gastrointestinal Infection Induces Long-Lived Microbiota-Specific T Cell Responses

Recognizing Escaped Commensals In order to coexist peacefully, the billions of bacteria in our gut and our immune system have reached a détente. An intestinal mucosal firewall exists, so bacteria remain localized to the gut, where the immune system is tightly regulated so that these bacteria are tolerated. Enteric infections, however, lead to a breach in this mucosal firewall, resulting in exposure of the peripheral immune system to the intestinal bacterial contents. What is the result? Using oral Toxoplasma gondii infection in mice, Hand et al. (p. 1553, published online 23 August) show that, besides the T. gondii–specific T cell response, a commensal bacteria–specific T cell response is elicited. The CD4+ T cell–specific response was tracked to a commensal-derived flagellin, and these T cells expanded after T. gondii infection and formed long-lived memory cells able to respond to subsequent challenges. Thus, enteric infections can lead to the formation of commensal bacteria–specific, long-lived memory T cells that reside throughout the body—which may play a role in intestinal pathologies such as inflammatory bowel disease. Enteric infections induce lasting adaptive immunity against commensal bacteria that may play a role in intestinal problems. The mammalian gastrointestinal tract contains a large and diverse population of commensal bacteria and is also one of the primary sites of exposure to pathogens. How the immune system perceives commensals in the context of mucosal infection is unclear. Here, we show that during a gastrointestinal infection, tolerance to commensals is lost, and microbiota-specific T cells are activated and differentiate to inflammatory effector cells. Furthermore, these T cells go on to form memory cells that are phenotypically and functionally consistent with pathogen-specific T cells. Our results suggest that during a gastrointestinal infection, the immune response to commensals parallels the immune response against pathogenic microbes and that adaptive responses against commensals are an integral component of mucosal immunity.

Diversity in the contribution of interleukin-10 to T-cell-mediated immune regulation.

Summary: Recent progress in our understanding of mechanisms by which the immunosuppressive cytokine interleukin‐10 (IL‐10) participates in an ever‐increasing diversity of T‐cell lineages to maintain immune homeostasis has broadened the framework for defining regulatory and effector T cells and has blurred the lines between them. In this review, we highlight established and emerging roles for IL‐10 produced by distinct CD4+ T‐cell lineages that underlie its non‐redundant role in curbing immune responses to the intestinal microbiota at steady state and its role to limit T‐cell‐driven inflammation in responses to pathogens.

IL-22–producing neutrophils contribute to antimicrobial defense and restitution of colonic epithelial integrity during colitis

IL-22 plays an important role in mucosal epithelial cell homeostasis. Using a dextran sodium sulfate-induced mouse model of acute colitis, we observed an IL-23–dependent up-regulation of IL-22 in the middle and distal colon at the onset of epithelial cell damage. This heightened IL-22 correlated with an influx of innate immune cells, suggesting an important role in colonic epithelial protection. Freshly isolated colon-infiltrating neutrophils produced IL-22 contingent upon IL-23 signaling, and IL-22 production was augmented by TNF-α. Importantly, the depletion of neutrophils resulted in diminished IL-22 levels in the colon, and the transfer of IL-22–competent neutrophils to Il22a-deficient mice protected the colonic epithelium from dextran sodium sulfate-induced damage. In addition, IL-22–producing neutrophils targeted colonic epithelial cells to up-regulate the antimicrobial peptides, RegIIIβ and S100A8. This study establishes a role for neutrophils in providing IL-22–dependent mucosal epithelial support that contributes to the resolution of colitis.

Intestinal Effector T Cells in Health and Disease

Crohns disease and ulcerative colitis are the two major forms of chronic relapsing inflammatory disorders of the human intestines collectively referred to as inflammatory bowel disease (IBD). Though a complex set of autoinflammatory disorders that can be precipitated by diverse genetic and environmental factors, a feature that appears common to IBD pathogenesis is a dysregulated effector T cell response to the commensal microbiota. Due to the heightened effector T cell activity in IBD, developmental and functional pathways that give rise to these cells are potential targets for therapeutic intervention. In this review, we highlight recent advances in our understanding of effector T cell biology in the context of intestinal immune regulation and speculate on their potential clinical significance.

Lineage-specific Effects of 1,25-Dihydroxyvitamin D3 on the Development of Effector CD4 T Cells

Vitamin D deficiency is implicated in autoimmune disease. We therefore evaluated the effects of 1α,25-dihydroxyvitamin D3 (1,25-D3), the active form of vitamin D, on the development of T helper 1 (Th1), Th17, and Th9 cells, which are implicated in the pathogenesis of different types of autoimmunity. 1,25-D3 compromised the development of Th17 and Th9 cells, including IL-22-expressing cells while simultaneously increasing the frequency of IL-10-competent cells. Relative to Th17 and Th9 cells, the effects of 1,25-D3 on Th1 cells were modest, reflecting the significantly reduced levels of the receptor for vitamin D in this lineage. The use of cells deficient in IL-10 or antibodies that block IL-10 signaling abolished the inhibitory effect of 1,25-D3 on Th9 cells but had no effect on inhibition of Th17 cell frequencies. Thus, the induction of IL-10 in cultures of Th9 cells is an important mechanism by which 1,25-D3 compromises Th9 development but does not explain inhibition of Th17 cells. A survey of select representatives of the Th17 transcriptome revealed that the levels of mRNA that encode RORγt, IL-17A, IL-17F, IL-23R, and IL-22, were reduced by 1,25-D3, whereas IL-21 and aryl hydrocarbon receptor mRNA remained unchanged. These data suggest that vitamin D deficiency may promote autoimmunity by favoring the inordinate production of Th17 and Th9 cells at the expense of regulatory IL-10-producing T cells.

Th17 cells give rise to Th1 cells that are required for the pathogenesis of colitis

Significance The Th17 subset of CD4+ T cells are important in the pathogenesis of inflammatory bowel disease (IBD), but the mechanisms of their actions, particularly the role of the development of IFN-γ–producing progeny of Th17 cells (Th1-like cells), are incompletely understood. Here, we show in a mouse model of Th17-driven IBD that transition of Th17 precursors to Th1-like cells is absolutely required for disease, because Th17 cells deficient in IFN-γ fail to induce intestinal inflammation. This transition is dependent on the transcription factors T-bet and, to a lesser extent, Stat4. These findings are relevant for clinical strategies that target IBD and suggest that focusing on both the Th17 and Th1-like arms of disease may be beneficial in therapy design. Th17 cells reactive to the enteric microbiota are central to the pathogenesis of certain types of inflammatory bowel disease. However, Th17 cells display substantial developmental plasticity, such that some progeny of Th17 cell precursors retain a predominantly IL-17A+ phenotype, whereas others extinguish IL-17 expression and acquire expression of IFN-γ, giving rise to “Th1-like” cells. It remains unclear what role these subsets play in inflammatory bowel disease. Using a Th17 transfer model of colitis, we found that IFN-γ–deficient Th17 cells retained an IL-17A+ phenotype and were unable to induce colitis in recipients. Development of disease required the transition of a subset of Th17 precursors to Th1-like cells and was contingent on the expression of both Stat4 and T-bet, but not the IL-12 or IFN-γ receptors. Moreover, Th17 cells could provide “help” for the development of pathogenic Th1 cells from naïve precursors. These results indicate that Th17 cells are potent mediators of colitis pathogenesis by dual mechanisms: by directly transitioning to Th1-like cells and by supporting the development of classic Th1 cells.

Role of TLR2-dependent IL-10 production in the inhibition of the initial IFN-γ T cell response to Porphyromonas gingivalis

P.g., a Gram‐negative bacterium, is one of the main etiological agents of the chronic inflammatory disease, periodontitis. Disease progression is thought to occur as a result of an inadequate immune response, which although happens locally, can also occur distally as a result of the dissemination of P.g. into the circulation. As IL‐10 and TLR2 are pivotal molecules in the immune response that P.g. elicits, we hypothesized that TLR2‐mediated IL‐10 production, following the initial systemic exposure to P.g., inhibits the IFN‐γ T cell response. To address this hypothesis, mice were primed with P.g., and the types of cells producing IL‐10 and the capacity of T cells to produce IFN‐γ following blocking or neutralization of IL‐10 were assessed. Our results showed that upon initial encounter with P.g., splenic T cells and CD11b+ cells produce IL‐10, which when neutralized, resulted in a substantial increase in IFN‐γ production by T cells. Furthermore, IL‐10 production was dependent on TLR2/1 signaling, partly in response to the major surface protein, FimA of P.g. In addition, P.g. stimulation resulted in the up‐regulation of PD‐1 and its ligand PD‐L1 on CD4 T cells and CD11b+ cells, respectively. Up‐regulation of PD‐1 was partially dependent on IL‐10 but independent of TLR2 or FimA. These results highlight the role of IL‐10 in inhibiting T cell responses to the initial systemic P.g. exposure and suggest multiple inhibitory mechanisms potentially used by P.g. to evade the hostˈs immune response, thus allowing its persistence in the host.

T Cell–Derived IL-10 Impairs Host Resistance to Mycobacterium tuberculosis Infection

Tuberculosis (TB), caused by Mycobacterium tuberculosis infection, is a leading cause of mortality and morbidity, causing ∼1.5 million deaths annually. CD4+ T cells and several cytokines, such as the Th1 cytokine IFN-γ, are critical in the control of this infection. Conversely, the immunosuppressive cytokine IL-10 has been shown to dampen Th1 cell responses to M. tuberculosis infection impairing bacterial clearance. However, the critical cellular source of IL-10 during M. tuberculosis infection is still unknown. Using IL-10 reporter mice, we show in this article that during the first 14 d of M. tuberculosis infection, the predominant cells expressing IL-10 in the lung were Ly6C+ monocytes. However, after day 21 postinfection, IL-10–expressing T cells were also highly represented. Notably, mice deficient in T cell–derived IL-10, but not mice deficient in monocyte-derived IL-10, showed a significant reduction in lung bacterial loads during chronic M. tuberculosis infection compared with fully IL-10–competent mice, indicating a major role for T cell–derived IL-10 in TB susceptibility. IL-10–expressing cells were detected among both CD4+ and CD8+ T cells, expressed high levels of CD44 and Tbet, and were able to coproduce IFN-γ and IL-10 upon ex vivo stimulation. Furthermore, during M. tuberculosis infection, Il10 expression in CD4+ T cells was partially regulated by both IL-27 and type I IFN signaling. Together, our data reveal that, despite the multiple immune sources of IL-10 during M. tuberculosis infection, activated effector T cells are the major source accounting for IL-10–induced TB susceptibility.