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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. 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.

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 colonie epithelial protection. Freshly isolated colon-infiltrating neutrophils produced IL-22 contingent upon IL-23 signaling, and IL-22 production was augmented by TNFa. Importantly, the depletion of neutrophils resulted in diminished IL-22 levels in the colon, and the transfer of IL-22-competent neutrophils to IL-22a-deficient mice protected the colonie epithelium from dextran sodium sulfate-induced damage. In addition, IL-22-producing neutrophils targeted colonie epithelial cells to up-regulate the antimicrobial peptides, Reglllp and S100A8. This study establishes a role for neutrophils in providing IL-22-dependent mucosal epithelial support that contributes to the resolution of colitis.

Malignant cells can induce the formation of lymphoid tissue–like structures that help the tumor evade host immunity. Many types of human tumors can suppress the immune system to enhance their survival. Some tumor cells escape immune detection by decreasing the expression of certain antigen-presenting proteins at their surface, rendering them invisible to cytotoxic T lymphocytes ( 1 ). But more often, tumors secrete proteins that inhibit effector T cell responses and promote the production of regulatory T cells that suppress immune responses ( 2 ). On page 749 of this issue, Shields et al. ( 3 ) identify another mechanism by which tumors deceive the immune system. Certain melanomas can reorganize their stromal microenvironment (the supportive connective tissue) into structures similar to lymphoid tissue of the immune system. This ingenious reconstruction recruits and maintains immune regulatory cells that promote tolerance and tumor progression.

Mycoplasma pneumoniae (Mp), a common cause of pneumonia, is associated with asthma; however, the mechanisms underlying this association remain unclear. We investigated the cellular immune response to Mp in mice. Intranasal inoculation with Mp elicited infiltration of the lungs with neutrophils, monocytes and macrophages. Systemic depletion of macrophages, but not neutrophils, resulted in impaired clearance of Mp from the lungs. Accumulation and activation of macrophages were decreased in the lungs of MyD88(-/-) mice and clearance of Mp was impaired, indicating that MyD88 is a key signaling protein in the anti-Mp response. MyD88-dependent signaling was also required for the Mp-induced activation of NFκB, which was essential for macrophages to eliminate the microbe in vitro. Thus, MyD88-NFκB signaling in macrophages is essential for clearance of Mp from the lungs.

Immunological T follicular helper (T FH ) cells are a subpopulation of CD4 + T cells that support B cell antibody production and the establishment of B cell memory. By contrast, non-T FH cells orchestrate enhanced innate immune cell functions at sites of pathogen encounter. The factors underlying differentiation into a T FH or non-T FH cell remain poorly understood, though there is evidence to suggest that the T cell growth factor interleukin-2 (IL-2) may play a role. Using IL-2 reporter mice, DiToro et al. show that naïve CD4 + T cells that produce IL-2 are fated to become T FH cells, whereas nonproducers, which receive IL-2, become non-T FH cells. The CD4 + T cell–fate decision was linked to T cell receptor strength—only those naïve CD4 + T cells that received the highest T cell receptor signals were able to produce IL-2. Science , this issue p. eaao2933 Expression of the cytokine IL-2 is linked with cell fate choice in immunological T cells. In response to infection, naïve CD4 + T cells differentiate into two subpopulations: T follicular helper (T FH ) cells, which support B cell antibody production, and non-T FH cells, which enhance innate immune cell functions. Interleukin-2 (IL-2), the major cytokine produced by naïve T cells, plays an important role in the developmental divergence of these populations. However, the relationship between IL-2 production and fate determination remains unclear. Using reporter mice, we found that differential production of IL-2 by naïve CD4 + T cells defined precursors fated for different immune functions. IL-2 producers, which were fated to become T FH cells, delivered IL-2 to nonproducers destined to become non-T FH cells. Because IL-2 production was limited to cells receiving the strongest T cell receptor (TCR) signals, a direct link between TCR-signal strength, IL-2 production, and T cell fate determination has been established.

Late-onset sepsis (LOS) is thought to result from systemic spread of commensal microbes from the intestines of premature infants. Clinical use of probiotics for LOS prophylaxis has varied owing to limited efficacy, reflecting an incomplete understanding of relationships between development of the intestinal microbiome, neonatal dysbiosis and LOS. Using a model of LOS, we found that components of the developing microbiome were both necessary and sufficient to prevent LOS. Maternal antibiotic exposure that eradicated or enriched transmission of Lactobacillus murinus exacerbated and prevented disease, respectively. Prophylactic administration of some, but not all Lactobacillus spp. was protective, as was administration of Escherichia coli . Intestinal oxygen level was a major driver of colonization dynamics, albeit via mechanisms distinct from those in adults. These results establish a link between neonatal dysbiosis and LOS, and provide a basis for rational selection of probiotics that modulate primary succession of the microbiome to prevent disease. Disrupting the normal maturation of the infant gut microbiota induced late-onset sepsis in mice, which could be prevented by administering specific bacteria.

Interleukin 22 (IL-22) has a non-redundant role in immune defence of the intestinal barrier 1 – 3 . T cells, but not innate lymphoid cells, have an indispensable role in sustaining the IL-22 signalling that is required for the protection of colonic crypts against invasion during infection by the enteropathogen Citrobacter rodentium 4 ( Cr ). However, the intestinal epithelial cell (IEC) subsets targeted by T cell-derived IL-22, and how T cell-derived IL-22 sustains activation in IECs, remain undefined. Here we identify a subset of absorptive IECs in the mid–distal colon that are specifically targeted by Cr and are differentially responsive to IL-22 signalling. Major histocompatibility complex class II (MHCII) expression by these colonocytes was required to elicit sustained IL-22 signalling from Cr -specific T cells, which was required to restrain Cr invasion. Our findings explain the basis for the regionalization of the host response to Cr and demonstrate that epithelial cells must elicit MHCII-dependent help from IL-22–producing T cells to orchestrate immune protection in the intestine. The murine enteropathogen Citrobacter rodentium targets a specific subset of absorptive intestinal epithelial cells in the mid–distal colon, which stimulate T cells to produce sustained IL-22 signals to mitigate further spread of the pathogen.

CD4 + regulatory T cells (T reg cells) that produce interleukin 10 (IL-10) are important contributors to immune homeostasis. We generated mice with a 'dual-reporter' system of the genes encoding IL-10 and the transcription factor Foxp3 to track T reg subsets based on coordinate or differential expression of these genes. Secondary lymphoid tissues, lung and liver had enrichment of Foxp3 + IL-10 − T reg cells, whereas the large and small intestine had enrichment of Foxp3 + IL-10 + and Foxp3 − IL-10 + T reg cells, respectively. Although negative for Il10 expression, both Foxp3 + and Foxp3 − CD4 + thymic precursor cells gave rise to peripheral IL-10 + T reg cells, with only Foxp3 − precursor cells giving rise to all T reg subsets. Each T reg subset developed in IL-10-deficient mice, but this was blocked by treatment with antibody to transforming growth factor-β. Thus, Foxp3 + and Foxp3 − precursor cells give rise to peripheral IL-10-expressing T reg cells by a mechanism dependent on transforming growth factor-β and independent of IL-10.

Interleukin 17 (IL-17)-producing helper T cells ([T.sub.H]17 cells) and [CD4.sup.+] inducible regulatory T cells ([iT.sub.reg] cells) emerge from an overlapping developmental program. In the intestines, the vitamin A metabolite retinoic acid (RA) is produced at steady state and acts as an important cofactor to induce [iT.sub.reg] cell development while potently inhibiting [T.sub.H]17 cell development. Here we found that IL-1 was needed to fully override RA-mediated expression of the transcription factor Foxp3 and induce protective [T.sub.H]17 cell responses. By repressing expression of the negative regulator SOCS3 dependent on the transcription factor NF-κB, IL-1 increased the amplitude and duration of phosphorylation of the transcription factor STAT3 induced by [T.sub.H]17-polarizing cytokines, which led to an altered balance in the binding of STAT3 and STAT5 to shared consensus sequences in developing T cells. Thus, IL-1 signaling modulated STAT activation downstream of cytokine receptors differently to control the [T.sub.H]17 cell--[iT.sub.reg] cell developmental fate.

iT reg cells and T H 17 cells share developmental steps, but their cellular fate depends on environmental cues. Weaver and colleagues show that IL-1 signaling alters the STAT3-STAT5 balance to skew cellular differentiation towards T H 17 CD4 + T cells. Interleukin 17 (IL-17)-producing helper T cells (T H 17 cells) and CD4 + inducible regulatory T cells (iT reg cells) emerge from an overlapping developmental program. In the intestines, the vitamin A metabolite retinoic acid (RA) is produced at steady state and acts as an important cofactor to induce iT reg cell development while potently inhibiting T H 17 cell development. Here we found that IL-1 was needed to fully override RA-mediated expression of the transcription factor Foxp3 and induce protective T H 17 cell responses. By repressing expression of the negative regulator SOCS3 dependent on the transcription factor NF-κB, IL-1 increased the amplitude and duration of phosphorylation of the transcription factor STAT3 induced by T H 17-polarizing cytokines, which led to an altered balance in the binding of STAT3 and STAT5 to shared consensus sequences in developing T cells. Thus, IL-1 signaling modulated STAT activation downstream of cytokine receptors differently to control the T H 17 cell–iT reg cell developmental fate.