Faculty Bibliography

Type-2-cell-mediated immune responses play a critical role in mediating both host-resistance and disease-tolerance mechanisms during helminth infections. Recently, type 2 cell responses have emerged as major regulators of tissue repair and metabolic homeostasis even under steady-state conditions. In this review, we consider how studies of helminth infection have contributed toward our expanding cellular and molecular understanding of type-2-cell-mediated immunity, as well as new areas such as the microbiome. By studying how these successful parasites form chronic infections without overt pathology, we are gaining additional insights into allergic and inflammatory diseases, as well as normal physiology.

Dendritic cells (DCs) are activated by pathogens to initiate and shape immune responses. We found that the activation of DCs by Plasmodium falciparum, the main causative agent of human malaria, induces a highly unusual phenotype by which DCs up-regulate costimulatory molecules and secretion of chemokines, but not of cytokines typical of inflammatory responses (IL-1beta, IL-6, IL-10, TNF). Similar results were obtained with DCs obtained from malaria-naive US donors and malaria-experienced donors from Mali. Contact-dependent cross-talk between the main DC subsets, plasmacytoid and myeloid DCs (mDCs) was necessary for increased chemokine and IFN-alpha secretion in response to the parasite. Despite the absence of inflammatory cytokine secretion, mDCs incubated with P. falciparum-infected erythrocytes activated antigen-specific naive CD4+ T cells to proliferate and secrete Th1-like cytokines. This unexpected response of human mDCs to P. falciparum exhibited a transcriptional program distinct from a classical LPS response, pointing to unique P. falciparum-induced activation pathways that may explain the uncharacteristic immune response to malaria.

BACKGROUND: Inflammatory bowel diseases (IBD) are believed to be driven by dysregulated interactions between the host and the gut microbiota. Our goal is to characterize and infer relationships between mucosal T cells, the host tissue environment, and microbial communities in patients with IBD who will serve as basis for mechanistic studies on human IBD. METHODS: We characterized mucosal CD4 T cells using flow cytometry, along with matching mucosal global gene expression and microbial communities data from 35 pinch biopsy samples from patients with IBD. We analyzed these data sets using an integrated framework to identify predictors of inflammatory states and then reproduced some of the putative relationships formed among these predictors by analyzing data from the pediatric RISK cohort. RESULTS: We identified 26 predictors from our combined data set that were effective in distinguishing between regions of the intestine undergoing active inflammation and regions that were normal. Network analysis on these 26 predictors revealed SAA1 as the most connected node linking the abundance of the genus Bacteroides with the production of IL17 and IL22 by CD4 T cells. These SAA1-linked microbial and transcriptome interactions were further reproduced with data from the pediatric IBD RISK cohort. CONCLUSIONS: This study identifies expression of SAA1 as an important link between mucosal T cells, microbial communities, and their tissue environment in patients with IBD. A combination of T cell effector function data, gene expression and microbial profiling can distinguish between intestinal inflammatory states in IBD regardless of disease types.

Atherosclerosis is a chronic inflammatory disease, and developing therapies to promote its regression is an important clinical goal. We previously established that atherosclerosis regression is characterized by an overall decrease in plaque macrophages and enrichment in markers of alternatively activated M2 macrophages. We have now investigated the origin and functional requirement for M2 macrophages in regression in normolipidemic mice that received transplants of atherosclerotic aortic segments. We compared plaque regression in WT normolipidemic recipients and those deficient in chemokine receptors necessary to recruit inflammatory Ly6Chi (Ccr2-/- or Cx3cr1-/-) or patrolling Ly6Clo (Ccr5-/-) monocytes. Atherosclerotic plaques transplanted into WT or Ccr5-/- recipients showed reduced macrophage content and increased M2 markers consistent with plaque regression, whereas plaques transplanted into Ccr2-/- or Cx3cr1-/- recipients lacked this regression signature. The requirement of recipient Ly6Chi monocyte recruitment was confirmed in cell trafficking studies. Fate-mapping and single-cell RNA sequencing studies also showed that M2-like macrophages were derived from newly recruited monocytes. Furthermore, we used recipient mice deficient in STAT6 to demonstrate a requirement for this critical component of M2 polarization in atherosclerosis regression. Collectively, these results suggest that continued recruitment of Ly6Chi inflammatory monocytes and their STAT6-dependent polarization to the M2 state are required for resolution of atherosclerotic inflammation and plaque regression.

It remains unclear whether activated inflammatory macrophages can adopt features of tissue-resident macrophages, or what mechanisms might mediate such a phenotypic conversion. Here we show that vitamin A is required for the phenotypic conversion of interleukin 4 (IL-4)-activated monocyte-derived F4/80intCD206+PD-L2+MHCII+ macrophages into macrophages with a tissue-resident F4/80hiCD206-PD-L2-MHCII-UCP1+ phenotype in the peritoneal cavity of mice and during the formation of liver granulomas in mice infected with Schistosoma mansoni. The phenotypic conversion of F4/80intCD206+ macrophages into F4/80hiCD206- macrophages was associated with almost complete remodeling of the chromatin landscape, as well as alteration of the transcriptional profiles. Vitamin A-deficient mice infected with S. mansoni had disrupted liver granuloma architecture and increased mortality, which indicates that failure to convert macrophages from the F4/80intCD206+ phenotype to F4/80hiCD206- may lead to dysregulated inflammation during helminth infection.

BACKGROUND: Adult survivors of childhood cancers such as acute lymphoblastic leukemia (ALL) have health problems that persist or develop years after cessation of therapy. These late effects include chronic inflammation-related comorbidities such as obesity and type 2 diabetes, but the underlying cause is poorly understood. RESULTS: We compared the anal microbiota composition of adult survivors of childhood ALL (N = 73) with healthy control subjects (N = 61). We identified an altered community with reduced microbial diversity in cancer survivors, who also exhibit signs of immune dysregulation including increased T cell activation and chronic inflammation. The bacterial community among cancer survivors was enriched for Actinobacteria (e.g. genus Corynebacterium) and depleted of Faecalibacterium, correlating with plasma concentrations of IL-6 and CRP and HLA-DR+CD4+ and HLA-DR+CD8+ T cells, which are established markers of inflammation and immune activation. CONCLUSIONS: We demonstrated a relationship between microbial dysbiosis and immune dysregulation in adult ALL survivors. These observations suggest that interventions that could restore microbial diversity may ameliorate chronic inflammation and, consequently, development of late effects of childhood cancer survivors.

Gut commensals profoundly affect host immunity and intestinal homeostasis, but the impact of commensal eukaryotic protozoans is poorly understood. In a recent Cell paper, Chudnovskiy et al. (2016) identify a commensal protozoan, Tritrichomonas musculis, that can enhance anti-bacterial defenses, but at the cost of increasing intestinal inflammation.

Increasing incidence of inflammatory bowel diseases such as Crohn's disease (CD) in developed nations is associated with changes to the environment, such as decreased prevalence of helminth colonization and alterations to the gut microbiota. We find that helminth infection protects mice deficient in the CD susceptibility geneNod2from intestinal abnormalities by inhibiting colonization with an inflammatoryBacteroidesspecies. Colonization resistance toBacteroideswas dependent on type-2 immunity, which promoted the establishment of a protective microbiota enriched in Clostridiales. Additionally, we show that individuals from helminth-endemic regions harbor a similar protective microbiota, and that deworming treatment reduced Clostridiales and increased Bacteroidales. These results support a model of the hygiene hypothesis whereby certain individuals are genetically susceptible to the consequences of a changing microbial environment.