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.
In response to infection, naïve CD4
T cells differentiate into two subpopulations: T follicular helper (T
) cells, which support B cell antibody production, and non-T
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
cells, delivered IL-2 to nonproducers destined to become non-T
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.
Tumor Immune Evasion Zindl, Carlene L.; Chaplin, David D.
Science (American Association for the Advancement of Science),
05/2010, Letnik:
328, Številka:
5979
Journal Article
Recenzirano
Odprti dostop
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.
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-beta. Thus, Foxp3(+) and Foxp3(-) precursor cells give rise to peripheral IL-10-expressing T(reg) cells by a mechanism dependent on transforming growth factor-beta and independent of IL-10.
Interleukin 22 (IL-22) has a non-redundant role in immune defence of the intestinal barrier
. 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
(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.
Interleukin (IL)-1β plays a critical role in IL-6β– and transforming growth factor β (TGFβ)–initiated Th17 differentiation and induction of Th17-mediated autoimmunity. However, the means by which ...IL-1 regulates various aspects of Th17 development remain poorly understood. We recently reported that IL-1β enhances STAT3 phosphorylation via NF-κB–mediated repression of SOCS3 to facilitate Il17 transcription and Th17 differentiation, identifying an effect of IL-1 signaling on proximal events of STAT3 signaling. Here, we show that IL-1β promotes STAT3 binding to key cis-elements that control IL-17 expression. Additionally, we demonstrate that the IL-1–induced NF-κB factor RelA directly regulates the Il17a/f loci in cooperation with STAT3. Our findings reveal that IL-1 impacts both proximal signaling events and downstream interactions between transcription factors and cis-regulatory elements to promote Il17a/f transcription and Th17 differentiation.
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.
Interleukin (IL)-22 is central to immune defense at barrier sites. We examined the contributions of innate lymphoid cell (ILC) and T cell-derived IL-22 during Citrobacter rodentium (C.r) infection ...using mice that both report Il22 expression and allow lineage-specific deletion. ILC-derived IL-22 activated STAT3 in C.r-colonized surface intestinal epithelial cells (IECs) but only temporally restrained bacterial growth. T cell-derived IL-22 induced a more robust and extensive activation of STAT3 in IECs, including IECs lining colonic crypts, and T cell-specific deficiency of IL-22 led to pathogen invasion of the crypts and increased mortality. This reflected a requirement for T cell-derived IL-22 for the expression of a host-protective transcriptomic program that included AMPs, neutrophil-recruiting chemokines, and mucin-related molecules, and it restricted IFNγ-induced proinflammatory genes. Our findings demonstrate spatiotemporal differences in the production and action of IL-22 by ILCs and T cells during infection and reveal an indispensable role for IL-22-producing T cells in the protection of the intestinal crypts.
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•ILCs and T cells localize to distinct microanatomic niches during C.r infection•IL-22+ innate cells target surface IECs to limit early bacterial colonization•IL-22+ T cells target crypt IECs to prevent C.r dissemination into colonic crypts•IL-22+ T cells amplify IEC-derived host defense genes and repress IFN-induced genes
Interleukin (IL)-22-producing innate and adaptive immune cells contribute to host protection at barrier sites. Zindl et al. reveal that IL-22+ ILCs and T cells are specialized for early versus late protection of the intestinal mucosa via distinct patterns of activation of intestinal epithelial cells: actions of ILCs are limited to the superficial IECs to limit early bacterial colonization, whereas IL-22+ CD4 T cells recruited to the LP uniquely target crypt IECs to restrain bacterial spread into the colonic crypts.
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