Interleukin-22 (IL-22) is central to host protection against bacterial infections at barrier sites. Both innate lymphoid cells (ILCs) and T cells produce IL-22. However, the specific contributions of ...CD4+ T cells and their developmental origins are unclear. We found that the enteric pathogen Citrobacter rodentium induced sequential waves of IL-22-producing ILCs and CD4+ T cells that were each critical to host defense during a primary infection. Whereas IL-22 production by ILCs was strictly IL-23 dependent, development of IL-22-producing CD4+ T cells occurred via an IL-6-dependent mechanism that was augmented by, but not dependent on, IL-23 and was dependent on both transcription factors T-bet and AhR. Transfer of CD4+ T cells differentiated with IL-6 in the absence of TGF-β (“Th22” cells) conferred complete protection of infected IL-22-deficient mice whereas transferred Th17 cells did not. These findings establish Th22 cells as an important component of mucosal antimicrobial host defense.
► IL-23-deficient mice are protected from low-dose Citrobacter rodentium infection ► CD4+ T cell-derived IL-22 is required for C. rodentium infection protection ► Th22 cells provide more effective antibacterial defense than do Th17 cells ► T-bet acts cooperatively with AhR in Il22 induction in Th22 cells
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.
Although the activator protein‐1 (AP‐1) factor Batf is required for Th17 cell development, its mechanisms of action to underpin the Th17 program are incompletely understood. Here, we find that Batf ...ensures Th17 cell identity in part by restricting alternative gene programs through its actions to restrain IL‐2 expression and IL‐2‐induced Stat5 activation. This, in turn, limits Stat5‐dependent recruitment of Ets1‐Runx1 factors to Th1‐ and Treg‐cell‐specific gene loci. Thus, in addition to pioneering regulatory elements in Th17‐specific loci, Batf acts indirectly to inhibit the assembly of a Stat5‐Ets1‐Runx1 complex that enhances the transcription of Th1‐ and Treg‐cell‐specific genes. These findings unveil an important role for Stat5‐Ets1‐Runx1 interactions in transcriptional networks that define alternate T cell fates and indicate that Batf plays an indispensable role in both inducing and maintaining the Th17 program through its actions to regulate the competing actions of Stat5‐assembled enhanceosomes that promote Th1‐ and Treg‐cell developmental programs.
Synopsis
In addition to its function as a pioneering transcription factor in Th17 development, Batf suppresses alternative T cell fates by down‐regulating IL‐2 receptor components thereby diminishing Stat5 activation and limiting the assembly of a Stat5‐Ets1‐Runx1 enhancer complex that promotes Th1– and Treg–specifying gene expression.
Batf inhibits IL‐2 expression early in Th17 development and limits IL‐2R and Stat5 expression in late stage Th17 cells.
Batf impairs Stat5‐dependent recruitment of Ets1 and Runx1 to Th1 and Treg‐cell gene loci, thus forming an enhanceosome that promotes lineage‐specifying gene transcription.
Sustained Batf expression is essential to prevent deviation to alternative cell fates and stabilize the Th17 phenotype.
Batf impairs assembly of a Stat5‐Ets1‐Runx1 complex that promotes Th1 and Treg‐cell developmental programs to maintain Th17 cell identity.
IL-6 is known to contribute to the differentiation of CD4
T cells into different subsets of effector T helper cells. Less is known about the potential of IL-6 in regulating CD8
T cell effector ...function. Here, we identify IL-6 as a master regulator of IL-21 in effector CD8
T cells. IL-6 promotes the differentiation of a subset of naive CD8
T cells that express IL-6R into a unique population of effector CD8
T cells characterized by the production of high levels of IL-21 and low levels of IFN-γ. Similar to CD4
T follicular helper (Tfh) cells, IL-21-producing CD8
T cells generated in the presence of IL-6 directly provide help to B cells to induce isotype switching. CD8
T cell-derived IL-21 contributes to the production of protective virus-specific IgG antibodies during influenza virus infection. Thus, this study reveals the presence of a new mechanism by which IL-6 regulates antibody production during viral infection, and a novel function of effector CD8
T cells in the protection against viruses.
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.
Display omitted
•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.
Citrobacter rodentium is a natural murine intestinal pathogen that shares a core set of virulence factors with the related human pathogens enteropathogenic Escherichia coli (EPEC) and ...enterohemorrhagic E. coli (EHEC). C. rodentium is now the most widely used small animal model for studying the molecular underpinnings of EPEC and EHEC infections in vivo, including: enterocyte attachment; virulence; colonization resistance; and mucosal immunity. In this review, we discuss type 3 immunity in the context of C. rodentium infection and discuss recent publications that use this model to understand how the innate and adaptive components of immunity intersect to mediate host protection against enteric pathogens and maintain homeostasis with the microbiota.
The global pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has highlighted the disparity between developed and developing countries for infectious disease surveillance ...and the sequencing of pathogen genomes. The majority of SARS-CoV-2 sequences published are from Europe, North America, and Asia. Between April 2020 and January 2022, 795 SARS-CoV-2-positive nares swabs from individuals in the U.S. Navy installation Camp Lemonnier, Djibouti, were collected, sequenced, and analyzed. In this study, we described the results of genomic sequencing and analysis for 589 samples, the first published viral sequences for Djibouti, including 196 cases of vaccine breakthrough infections. This study contributes to the knowledge base of circulating SARS-CoV-2 lineages in the under-sampled country of Djibouti, where only 716 total genome sequences are available at time of publication. Our analysis resulted in the detection of circulating variants of concern, mutations of interest in lineages in which those mutations are not common, and emerging spike mutations.
Vibrio parahaemolyticus is an aquatic halophilic bacterium that occupies estuarine and coastal marine environments, and is a leading cause of seafood-borne food poisoning cases. To investigate the ...environmental reservoir and potential gene flow that occurs among V. parahaemolyticus isolates, the virulence-associated gene content and genome diversity of a collection of 133 V. parahaemolyticus isolates were analyzed. Phylogenetic analysis of housekeeping genes, and pulsed-field gel electrophoresis, demonstrated that there is genetic similarity among V. parahaemolyticus clinical and environmental isolates. Whole-genome sequencing and comparative analysis of six representative V. parahaemolyticus isolates was used to identify genes that are unique to the clinical and environmental isolates examined. Comparative genomics demonstrated an O3:K6 environmental isolate, AF91, which was cultured from sediment collected in Florida in 2006, has significant genomic similarity to the post-1995 O3:K6 isolates. However, AF91 lacks the majority of the virulence-associated genes and genomic islands associated with these highly virulent post-1995 O3:K6 genomes. These findings demonstrate that although they do not contain most of the known virulence-associated regions, some V. parahaemolyticus environmental isolates exhibit significant genetic similarity to clinical isolates. This highlights the dynamic nature of the V. parahaemolyticus genome allowing them to transition between aquatic and host-pathogen states.
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 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 restricted IFNγ–induced pro-inflammatory genes. Our findings demonstrate spatiotemporal differences in the production and action of IL-22 by ILCs and T cells during infection and reveal an indispenable role for IL-22–producing T cells in the protection of the intestinal crypts.
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.
PDF
