Assistant Professor, Microbiology & Immunology
Honors & Awards
Pathway to Independence Award (K99/R00), National Institute of Diabetes and Digestive and Kidney Diseases (2019-current)
Cancer Research Institute-Irvington Postdoctoral Fellow, Cancer Research Institute (2016-2019)
Postdoctoral Research Associate, Washington University in St. Louis, Department of Pathology and Immunology (2021)
Ph.D., University of California - San Francisco, Biomedical Sciences (2014)
B.S., University of California - Los Angeles, Marine Biology/Biochemistry (2005)
The aryl hydrocarbon receptor instructs the immunomodulatory profile of a subset of Clec4a4+ eosinophils unique to the small intestine.
Proceedings of the National Academy of Sciences of the United States of America
2022; 119 (23): e2204557119
SignificanceEosinophils contribute to type 2 immunity against helminths and allergens. The small intestine harbors eosinophils with incompletely understood pathophysiological roles. Here, we show that intestinal eosinophils include two subsets. One expresses the inhibitory receptor Clec4a4 and the inhibitory ligand PD-L1 and is unique to the small intestine; the other manifests a proinflammatory phenotype. Both subsets are blood derived. Remarkably, Clec4a4+ eosinophils were instructed by the aryl hydrocarbon receptor (AHR), a ligand-activated transcription factor that imprints many gut immune cells. Selective AHR deletion in eosinophils depleted Clec4a4+ eosinophils, augmented innate lymphocytes producing type 2 cytokines, and enhanced helminth clearance. We conclude that Clec4a4+ eosinophils have immunomodulatory functions, which could be harnessed for the therapy of food allergies and eosinophilic gastrointestinal disorders.
View details for DOI 10.1073/pnas.2204557119
View details for PubMedID 35653568
Whole-genome profiling of DNA methylation and hydroxymethylation identifies distinct regulatory programs among innate lymphocytes.
Innate lymphocytes encompass a diverse array of phenotypic identities with specialized functions. DNA methylation and hydroxymethylation are essential for epigenetic fidelity and fate commitment. The landscapes of these modifications are unknown in innate lymphocytes. Here, we characterized the whole-genome distribution of methyl-CpG and 5-hydroxymethylcytosine (5hmC) in mouse innate lymphoid cell 3 (ILC3), ILC2 and natural killer (NK) cells. We identified differentially methylated regions (DMRs) and differentially hydroxymethylated regions (DHMRs) between ILC and NK cell subsets and correlated them with transcriptional signatures. We associated lineage-determining transcription factors (LDTFs) with demethylation and demonstrated unique patterns of DNA methylation/hydroxymethylation in relationship to open chromatin regions (OCRs), histone modifications and TF-binding sites. We further identified an association between hydroxymethylation and NK cell superenhancers (SEs). Using mice lacking the DNA hydroxymethylase TET2, we showed the requirement for TET2 in optimal production of hallmark cytokines by ILC3s and interleukin-17A (IL-17A) by inflammatory ILC2s. These findings provide a powerful resource for studying innate lymphocyte epigenetic regulation and decode the regulatory logic governing their identity.
View details for DOI 10.1038/s41590-022-01164-8
View details for PubMedID 35332328
Spatial distribution of LTi-like cells in intestinal mucosa regulates type 3 innate immunity.
Proceedings of the National Academy of Sciences of the United States of America
2021; 118 (23)
Lymphoid tissue inducer (LTi)-like cells are tissue resident innate lymphocytes that rapidly secrete cytokines that promote gut epithelial integrity and protect against extracellular bacterial infections.Here, we report that the retention of LTi-like cells in conventional solitary intestinal lymphoid tissue (SILT) is essential for controlling LTi-like cell function and is maintained by expression of the chemokine receptor CXCR5. Deletion of Cxcr5 functionally unleashed LTi-like cells in a cell intrinsic manner, leading to uncontrolled IL-17 and IL-22 production. The elevated production of IL-22 in Cxcr5-deficient mice improved gut barrier integrity and protected mice during infection with the opportunistic pathogen Clostridium difficile Interestingly, Cxcr5 -/- mice developed LTi-like cell aggregates that were displaced from their typical niche at the intestinal crypt, and LTi-like cell hyperresponsiveness was associated with the local formation of this unconventional SILT. Thus, LTi-like cell positioning within mucosa controls their activity via niche-specific signals that temper cytokine production during homeostasis.
View details for DOI 10.1073/pnas.2101668118
View details for PubMedID 34083442
Heterogeneity of meningeal B cells reveals a lymphopoietic niche at the CNS borders.
Science (New York, N.Y.)
The meninges contain adaptive immune cells that provide immunosurveillance of the CNS. These cells are thought to derive from the systemic circulation. Through single-cell analyses, confocal imaging, bone marrow chimeras, and parabiosis experiments, we show that meningeal B cells derive locally from the calvaria, which harbors a bone marrow niche for hematopoiesis. B cells reach the meninges from the calvaria through specialized vascular connections. This calvarial-meningeal path of B cell development may provide the CNS with a constant supply of B cells educated by CNS antigens. Conversely, we show that a subset of antigen-experienced B cells that populate the meninges in aging mice are blood-borne. These results identify a private source for meningeal B cells. which may help maintain immune privilege within the CNS.
View details for DOI 10.1126/science.abf9277
View details for PubMedID 34083450
Indole-3-Carbinol-Dependent Aryl Hydrocarbon Receptor Signaling Attenuates the Inflammatory Response in Experimental Necrotizing Enterocolitis.
2021; 5 (4): 193-209
Necrotizing enterocolitis (NEC) causes significant morbidity and mortality in premature infants; therefore, the identification of therapeutic and preventative strategies against NEC remains a high priority. The ligand-dependent transcription factor aryl hydrocarbon receptor (AhR) is well known to contribute to the regulation of intestinal microbial communities and amelioration of intestinal inflammation. However, the role of AhR signaling in NEC is unclear. Experimental NEC was induced in 4-d-old wild-type mice or mice lacking AhR expression in the intestinal epithelial cells or AhR expression in CD11c+ cells (AhRΔCD11c) by subjecting animals to twice daily hypoxic stress and gavage feeding with formula supplemented with LPS and enteric bacteria. During NEC, compared with wild-type mice treated with vehicle, littermates treated with an AhR proligand, indole-3-carbinol, had reduced expression of Il1b and Marco, a scavenger receptor that mediates dendritic cell activation and the recognition and clearance of bacterial pathogens by macrophages. Furthermore, indole-3-carbinol treatment led to the downregulation of genes involved in cytokine and chemokine, as revealed by pathway enrichment analysis. AhR expression in the intestinal epithelial cells and their cre-negative mouse littermates were similarly susceptible to experimental NEC, whereas AhRΔCD11c mice with NEC exhibited heightened inflammatory responses compared with their cre-negative mouse littermates. In seeking to determine the mechanisms involved in this increased inflammatory response, we identified the Tim-4- monocyte-dependent subset of macrophages as increased in AhRΔCD11c mice compared with their cre-negative littermates. Taken together, these findings demonstrate the potential for AhR ligands as a novel immunotherapeutic approach to the management of this devastating disease.
View details for DOI 10.4049/immunohorizons.2100018
View details for PubMedID 33906960
- Group 2 Innate Lymphoid Cells Induce Antibody Production in Gastric Tissue. Trends in immunology 2020; 41 (8): 643-645
STING Gain-of-Function Disrupts Lymph Node Organogenesis and Innate Lymphoid Cell Development in Mice.
2020; 31 (11): 107771
STING gain-of-function causes autoimmunity and immunodeficiency in mice and STING-associated vasculopathy with onset in infancy (SAVI) in humans. Here, we report that STING gain-of-function in mice prevents development of lymph nodes and Peyer's patches. We show that the absence of secondary lymphoid organs is associated with diminished numbers of innate lymphoid cells (ILCs), including lymphoid tissue inducer (LTi) cells. Although wild-type (WT) α4β7+ progenitors differentiate efficiently into LTi cells, STING gain-of-function progenitors do not. Furthermore, STING gain-of-function impairs development of all types of ILCs. Patients with STING gain-of-function mutations have fewer ILCs, although they still have lymph nodes. In mice, expression of the STING mutant in RORγT-positive lineages prevents development of lymph nodes and reduces numbers of LTi cells. RORγT lineage-specific expression of STING gain-of-function also causes lung disease. Since RORγT is expressed exclusively in LTi cells during fetal development, our findings suggest that STING gain-of-function prevents lymph node organogenesis by reducing LTi cell numbers in mice.
View details for DOI 10.1016/j.celrep.2020.107771
View details for PubMedID 32553167
View details for PubMedCentralID PMC7372600
Insulin-Like Growth Factors Are Key Regulators of T Helper 17 Regulatory T Cell Balance in Autoimmunity.
2020; 52 (4): 650-667.e10
Appropriate balance of T helper 17 (Th17) and regulatory T (Treg) cells maintains immune tolerance and host defense. Disruption of Th17-Treg cell balance is implicated in a number of immune-mediated diseases, many of which display dysregulation of the insulin-like growth factor (IGF) system. Here, we show that, among effector T cell subsets, Th17 and Treg cells selectively expressed multiple components of the IGF system. Signaling through IGF receptor (IGF1R) activated the protein kinase B-mammalian target of rapamycin (AKT-mTOR) pathway, increased aerobic glycolysis, favored Th17 cell differentiation over that of Treg cells, and promoted a heightened pro-inflammatory gene expression signature. Group 3 innate lymphoid cells (ILC3s), but not ILC1s or ILC2s, were similarly responsive to IGF signaling. Mice with deficiency of IGF1R targeted to T cells failed to fully develop disease in the experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis. Thus, the IGF system represents a previously unappreciated pathway by which type 3 immunity is modulated and immune-mediated pathogenesis controlled.
View details for DOI 10.1016/j.immuni.2020.03.013
View details for PubMedID 32294406
View details for PubMedCentralID PMC8078727
ILC2s are the predominant source of intestinal ILC-derived IL-10.
The Journal of experimental medicine
2020; 217 (2)
Although innate lymphoid cells (ILCs) functionally analogous to T helper type 1 (Th1), Th2, and Th17 cells are well characterized, an ILC subset strictly equivalent to IL-10-secreting regulatory T cells has only recently been proposed. Here, we report the absence of an intestinal regulatory ILC population distinct from group 1 ILCs (ILC1s), ILC2s, and ILC3s in (1) mice bred in our animal facility; (2) mice from The Jackson Laboratory, Taconic Biosciences, and Charles River Laboratories; and (3) mice subjected to intestinal inflammation. Instead, a low percentage of intestinal ILC2s produced IL-10 at steady state. A screen for putative IL-10 elicitors revealed that IL-2, IL-4, IL-27, IL-10, and neuromedin U (NMU) increased IL-10 production in activated intestinal ILC2s, while TL1A suppressed IL-10 production. Secreted IL-10 further induced IL-10 production in ILC2s through a positive feedback loop. In summary, ILC2s provide an inducible source of IL-10 in the gastrointestinal tract, whereas ILCregs are not a generalizable immune cell population in mice.
View details for DOI 10.1084/jem.20191520
View details for PubMedID 31699824
View details for PubMedCentralID PMC7041711
Circadian rhythm-dependent and circadian rhythm-independent impacts of the molecular clock on type 3 innate lymphoid cells.
2019; 4 (40)
Many gut functions are attuned to circadian rhythm. Intestinal group 3 innate lymphoid cells (ILC3s) include NKp46+ and NKp46- subsets, which are RORγt dependent and provide mucosal defense through secretion of interleukin-22 (IL-22) and IL-17. Because ILC3s highly express some key circadian clock genes, we investigated whether ILC3s are also attuned to circadian rhythm. We noted circadian oscillations in the expression of clock and cytokine genes, such as REV-ERBα, IL-22, and IL-17, whereas acute disruption of the circadian rhythm affected cytokine secretion by ILC3s. Because of prominent and rhythmic expression of REV-ERBα in ILC3s, we also investigated the impact of constitutive deletion of REV-ERBα, which has been previously shown to inhibit the expression of a RORγt repressor, NFIL3, while also directly antagonizing DNA binding of RORγt. Development of the NKp46+ ILC3 subset was markedly impaired, with reduced cell numbers, RORγt expression, and IL-22 production in REV-ERBα-deficient mice. The NKp46- ILC3 subsets developed normally, potentially due to compensatory expression of other clock genes, but IL-17 secretion paradoxically increased, probably because RORγt was not antagonized by REV-ERBα. We conclude that ILC3s are attuned to circadian rhythm, but clock regulator REV-ERBα also has circadian-independent impacts on ILC3 development and functions due to its roles in the regulation of RORγt.
View details for DOI 10.1126/sciimmunol.aay7501
View details for PubMedID 31586012
View details for PubMedCentralID PMC6911370
Subsets of ILC3-ILC1-like cells generate a diversity spectrum of innate lymphoid cells in human mucosal tissues.
2019; 20 (8): 980-991
Innate lymphoid cells (ILCs) are tissue-resident lymphocytes categorized on the basis of their core regulatory programs and the expression of signature cytokines. Human ILC3s that produce the cytokine interleukin-22 convert into ILC1-like cells that produce interferon-γ in vitro, but whether this conversion occurs in vivo remains unclear. In the present study we found that ILC3s and ILC1s in human tonsils represented the ends of a spectrum that included additional discrete subsets. RNA velocity analysis identified an intermediate ILC3-ILC1 cluster, which had strong directionality toward ILC1s. In humanized mice, the acquisition of ILC1 features by ILC3s showed tissue dependency. Chromatin studies indicated that the transcription factors Aiolos and T-bet cooperated to repress regulatory elements active in ILC3s. A transitional ILC3-ILC1 population was also detected in the human intestine. We conclude that ILC3s undergo conversion into ILC1-like cells in human tissues in vivo, and that tissue factors and Aiolos were required for this process.
View details for DOI 10.1038/s41590-019-0425-y
View details for PubMedID 31209406
View details for PubMedCentralID PMC6685551
The Tumor Necrosis Factor Superfamily Member RANKL Suppresses Effector Cytokine Production in Group 3 Innate Lymphoid Cells.
2018; 48 (6): 1208-1219.e4
While signals that activate group 3 innate lymphoid cells (ILC3s) have been described, the factors that negatively regulate these cells are less well understood. Here we found that the tumor necrosis factor (TNF) superfamily member receptor activator of nuclear factor κB ligand (RANKL) suppressed ILC3 activity in the intestine. Deletion of RANKL in ILC3s and T cells increased C-C motif chemokine receptor 6 (CCR6)+ ILC3 abundance and enhanced production of interleukin-17A (IL-17A) and IL-22 in response to IL-23 and during infection with the enteric murine pathogen Citrobacter rodentium. Additionally, CCR6+ ILC3s produced higher amounts of the master transcriptional regulator RORγt at steady state in the absence of RANKL. RANKL-mediated suppression was independent of T cells, and instead occurred via interactions between CCR6+ ILC3s that expressed both RANKL and its receptor, RANK. Thus, RANK-RANKL interactions between ILC3s regulate ILC3 abundance and activation, suggesting that cell clustering may control ILC3 activity.
View details for DOI 10.1016/j.immuni.2018.04.012
View details for PubMedID 29858011
View details for PubMedCentralID PMC6086389
Natural Killer Cells Control Tumor Growth by Sensing a Growth Factor.
2018; 172 (3): 534-548.e19
Many tumors produce platelet-derived growth factor (PDGF)-DD, which promotes cellular proliferation, epithelial-mesenchymal transition, stromal reaction, and angiogenesis through autocrine and paracrine PDGFRβ signaling. By screening a secretome library, we found that the human immunoreceptor NKp44, encoded by NCR2 and expressed on natural killer (NK) cells and innate lymphoid cells, recognizes PDGF-DD. PDGF-DD engagement of NKp44 triggered NK cell secretion of interferon gamma (IFN)-γ and tumor necrosis factor alpha (TNF-α) that induced tumor cell growth arrest. A distinctive transcriptional signature of PDGF-DD-induced cytokines and the downregulation of tumor cell-cycle genes correlated with NCR2 expression and greater survival in glioblastoma. NKp44 expression in mouse NK cells controlled the dissemination of tumors expressing PDGF-DD more effectively than control mice, an effect enhanced by blockade of the inhibitory receptor CD96 or CpG-oligonucleotide treatment. Thus, while cancer cell production of PDGF-DD supports tumor growth and stromal reaction, it concomitantly activates innate immune responses to tumor expansion.
View details for DOI 10.1016/j.cell.2017.11.037
View details for PubMedID 29275861
View details for PubMedCentralID PMC6684025
SMAD4 impedes the conversion of NK cells into ILC1-like cells by curtailing non-canonical TGF-β signaling.
2017; 18 (9): 995-1003
Among the features that distinguish type 1 innate lymphoid cells (ILC1s) from natural killer (NK) cells is a gene signature indicative of 'imprinting' by cytokines of the TGF-β family. We studied mice in which ILC1s and NK cells lacked SMAD4, a signal transducer that facilitates the canonical signaling pathway common to all cytokines of the TGF-β family. While SMAD4 deficiency did not affect ILC1 differentiation, NK cells unexpectedly acquired an ILC1-like gene signature and were unable to control tumor metastasis or viral infection. Mechanistically, SMAD4 restrained non-canonical TGF-β signaling mediated by the cytokine receptor TGFβR1 in NK cells. NK cells from a SMAD4-deficient person affected by polyposis were also hyper-responsive to TGF-β. These results identify SMAD4 as a previously unknown regulator that restricts non-canonical TGF-β signaling in NK cells.
View details for DOI 10.1038/ni.3809
View details for PubMedID 28759002
View details for PubMedCentralID PMC5712491
IL-15 sustains IL-7R-independent ILC2 and ILC3 development.
2017; 8: 14601
The signals that maintain tissue-resident innate lymphoid cells (ILC) in different microenvironments are incompletely understood. Here we show that IL-7 receptor (IL-7R) is not strictly required for the development of any ILC subset, as residual cells persist in the small intestinal lamina propria (siLP) of adult and neonatal Il7ra-/- mice. Il7ra-/- ILC2 primarily express an ST2- phenotype, but are not inflammatory ILC2. CCR6+ ILC3, which express higher Bcl-2 than other ILC3, are the most abundant subset in Il7ra-/- siLP. All ILC subsets are functionally competent in vitro, and are sufficient to provide enhanced protection to infection with C. rodentium. IL-15 equally sustains wild-type and Il7ra-/- ILC survival in vitro and compensates for IL-7R deficiency, as residual ILCs are depleted in mice lacking both molecules. Collectively, these data demonstrate that siLP ILCs are not completely IL-7R dependent, but can persist partially through IL-15 signalling.
View details for DOI 10.1038/ncomms14601
View details for PubMedID 28361874
View details for PubMedCentralID PMC5380969
Innate lymphoid cell function in the context of adaptive immunity.
2016; 17 (7): 783-9
Innate lymphoid cells (ILCs) are a family of innate immune cells that have diverse functions during homeostasis and disease. Subsets of ILCs have phenotypes that mirror those of polarized helper T cell subsets in their expression of core transcription factors and effector cytokines. Given the similarities between these two classes of lymphocytes, it is important to understand which functions of ILCs are specialized and which are redundant with those of T cells. Here we discuss genetic mouse models that have been used to delineate the contributions of ILCs versus those of T cells and review the current understanding of the specialized in vivo functions of ILCs.
View details for DOI 10.1038/ni.3484
View details for PubMedID 27328008
View details for PubMedCentralID PMC5156404
Transforming Growth Factor-β Signaling Guides the Differentiation of Innate Lymphoid Cells in Salivary Glands.
2016; 44 (5): 1127-39
The signals guiding differentiation of innate lymphoid cells (ILCs) within tissues are not well understood. Salivary gland (SG) ILCs as well as liver and intestinal intraepithelial ILC1 have markers that denote tissue residency and transforming growth factor-β (TGF-β) imprinting. We deleted Tgfbr2 in cells expressing the ILC and NK marker NKp46 and found that SG ILCs were reduced in number. They lost distinct tissue markers, such as CD49a, and the effector molecules TRAIL and CD73. Expression of the transcription factor Eomes, which promotes NK cell differentiation, was elevated. Conversely, Eomes deletion in NKp46(+) cells enhanced TGF-β-imprinting of SG ILCs. Thus, TGF-β induces SG ILC differentiation by suppressing Eomes. TGF-β acted through a JNK-dependent, Smad4-independent pathway. Transcriptome analysis demonstrated that SG ILCs had characteristic of both NK cells and ILC1. Finally, TGF-β imprinting of SG ILCs was synchronized with SG development, highlighting the impact of tissue microenvironment on ILC development.
View details for DOI 10.1016/j.immuni.2016.03.007
View details for PubMedID 27156386
View details for PubMedCentralID PMC5114145
Identification and distribution of developing innate lymphoid cells in the fetal mouse intestine.
2015; 16 (2): 153-60
Fetal lymphoid tissue inducer (LTi) cells are required for lymph node and Peyer's patch (PP) organogenesis, but where these specialized group 3 innate lymphoid cells (ILC3s) develop remains unclear. Here, we identify extrahepatic arginase-1(+) Id2(+) fetal ILC precursors that express a transitional developmental phenotype (ftILCPs) and differentiate into ILC1s, ILC2s and ILC3s in vitro. These cells populate the intestine by embryonic day (E) 13.5 and, before PP organogenesis (E14.5-15), are broadly dispersed in the proximal gut, correlating with regions where PPs first develop. At E16.5, after PP development begins, ftILCPs accumulate at PP anlagen in a lymphotoxin-α-dependent manner. Thus, ftILCPs reside in the intestine during PP development, where they aggregate at PP anlagen after stromal cell activation and become a localized source of ILC populations.
View details for DOI 10.1038/ni.3057
View details for PubMedID 25501629
View details for PubMedCentralID PMC4297560
Leukotriene B4 amplifies eosinophil accumulation in response to nematodes.
The Journal of experimental medicine
2014; 211 (7): 1281-8
Eosinophil accumulation is a defining feature of the immune response to parasitic worm infection. Tissue-resident cells, such as epithelial cells, are thought to initiate eosinophil recruitment. However, direct recognition of worms by eosinophils has not been explored as a mechanism for amplifying eosinophil accumulation. Here, we report that eosinophils rapidly migrate toward diverse nematode species in three-dimensional culture. These include the mammalian parasite Nippostrongylus brasiliensis and the free-living nematode Caenorhabditis elegans. Surprisingly, collective migration toward worms requires paracrine leukotriene B4 signaling between eosinophils. In contrast, neutrophils show a minimal response to nematodes, yet are able to undergo robust leukotriene-dependent migration toward IgG-coated beads. We further demonstrate that eosinophils accumulate around C. elegans in the lungs of mice. This response is not dependent on bacterial products, CCR3, or complement activation. However, mice deficient in leukotriene signaling show markedly attenuated eosinophil accumulation after injection of C. elegans or N. brasiliensis. Our findings establish that nematode-derived signals can directly induce leukotriene production by eosinophils and that leukotriene signaling is a major contributor to nematode-induced eosinophil accumulation in the lung. The similarity of the eosinophil responses to diverse nematode species suggests that conserved features of nematodes are recognized during parasite infection.
View details for DOI 10.1084/jem.20132336
View details for PubMedID 24889202
View details for PubMedCentralID PMC4076593
Type 2 innate lymphoid cells constitutively express arginase-I in the naive and inflamed lung
JOURNAL OF LEUKOCYTE BIOLOGY
2013; 94 (5): 877–84
Arg1 is produced by AAMs and is proposed to have a regulatory role during asthma and allergic inflammation. Here, we use an Arg1 reporter mouse to identify additional cellular sources of the enzyme in the lung. We demonstrate that ILC2s express Arg1 at rest and during infection with the migratory helminth Nippostrongylus brasiliensis. In contrast to AAMs, which express Arg1 following IL-4/IL-13-mediated STAT6 activation, ILC2s constitutively express the enzyme in a STAT6-independent manner. Although ILC2s deficient in the IL-33R subunit T1/ST2 maintain Arg1 expression, IL-33 can regulate total lung Arg1 by expanding the ILC2 population and by activating macrophages indirectly via STAT6. Finally, we find that ILC2 Arg1 does not mediate ILC2 accumulation, ILC2 production of IL-5 and IL-13, or collagen production during N. brasiliensis infection. Thus, ILC2s are a novel source of Arg1 in resting tissue and during allergic inflammation.
View details for DOI 10.1189/jlb.0213084
View details for Web of Science ID 000330537700004
View details for PubMedID 23924659
View details for PubMedCentralID PMC3800063
Subsets of Nonclonal Neighboring CD4(+) T Cells Specifically Regulate the Frequency of Individual Antigen-Reactive T Cells
2012; 37 (4): 735–46
After an immune response, the expanded population of antigen-specific CD4(+) T cells contract to steady state levels. We have found that the contraction is neither cell-autonomous nor mediated by competition for generic trophic factors, but regulated by relatively rare subsets of neighboring CD4(+) T cells not necessarily of a conventional regulatory T cell lineage. These regulators, referred to as deletors, specifically limit the frequency of particular antigen-specific T cells even though they are not reactive to the same agonist as their targets. Instead, an isolated deletor could outcompete the target for recognition of a shared, nonstimulatory endogenous peptide-MHC ligand. This mechanism was sufficient to prevent even agonist-driven autoimmune disease in a lymphopenic environment. Such a targeted regulation of homeostasis within narrow colonies of T cells with related TCR specificities for subthreshold ligands might help to prevent the loss of unrelated TCRs during multiple responses, preserving the valuable diversity of the repertoire.
View details for DOI 10.1016/j.immuni.2012.08.008
View details for Web of Science ID 000310185400017
View details for PubMedID 23021952
View details for PubMedCentralID PMC3478444
Divergent expression patterns of IL-4 and IL-13 define unique functions in allergic immunity
2012; 13 (1): 58–U83
Interleukin 4 (IL-4) and IL-13 are critical for responses to parasitic helminthes. We used genetically engineered reporter mice to assess the temporal and spatial production of these cytokines in vivo. In lymph nodes, IL-4, but not IL-13, was made by follicular helper T cells (T(FH) cells). In contrast, tissue type 2 helper T cells (T(H)2 cells) produced both cytokines. There was also divergent production of IL-4 and IL-13 among cells of the innate immune system, whereby basophils produced IL-4, whereas innate helper type 2 cells (Ih2 cells) produced IL-13. IL-13 production by T(H)2 and Ih2 cells was dependent on the transcription factor GATA-3, which was present in large amounts in these cells, and in contrast to the small amount of GATA-3 in T(FH) cells and basophils. The distinct localization and cellular expression of IL-4 and IL-13 explains their unique roles during allergic immunity.
View details for DOI 10.1038/ni.2182
View details for Web of Science ID 000298412800012
View details for PubMedID 22138715
View details for PubMedCentralID PMC3242938
Genetic analysis of basophil function in vivo
2011; 12 (6): 527–U243
Contributions by basophils to allergic and helminth immunity remain incompletely defined. Using sensitive interleukin 4 (Il4) reporter alleles, we demonstrate here that basophil IL-4 production occurs by a CD4(+) T cell-dependent process restricted to the peripheral tissues affected. We genetically marked and achieved specific deletion of basophils and found that basophils did not mediate T helper type 2 (T(H)2) priming in vivo. Two-photon imaging confirmed that basophils did not interact with antigen-specific T cells in lymph nodes but engaged in prolonged serial interactions with T cells in lung tissues. Although targeted deletion of IL-4 and IL-13 in either CD4(+) T cells or basophils had a minimal effect on worm clearance, deletion from both lineages demonstrated a nonredundant role for basophil cytokines in primary helminth immunity.
View details for DOI 10.1038/ni.2036
View details for Web of Science ID 000290707100013
View details for PubMedID 21552267
View details for PubMedCentralID PMC3271435
Eosinophils Sustain Adipose Alternatively Activated Macrophages Associated with Glucose Homeostasis
2011; 332 (6026): 243-247
Eosinophils are associated with helminth immunity and allergy, often in conjunction with alternatively activated macrophages (AAMs). Adipose tissue AAMs are necessary to maintain glucose homeostasis and are induced by the cytokine interleukin-4 (IL-4). Here, we show that eosinophils are the major IL-4-expressing cells in white adipose tissues of mice, and, in their absence, AAMs are greatly attenuated. Eosinophils migrate into adipose tissue by an integrin-dependent process and reconstitute AAMs through an IL-4- or IL-13-dependent process. Mice fed a high-fat diet develop increased body fat, impaired glucose tolerance, and insulin resistance in the absence of eosinophils, and helminth-induced adipose tissue eosinophilia enhances glucose tolerance. Our results suggest that eosinophils play an unexpected role in metabolic homeostasis through maintenance of adipose AAMs.
View details for DOI 10.1126/science.1201475
View details for Web of Science ID 000289251100054
View details for PubMedID 21436399
View details for PubMedCentralID PMC3144160
Sex Differences in Ethanol-Induced Hypothermia in Ethanol-Naive and Ethanol-Dependent/Withdrawn Rats
ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH
2009; 33 (1): 60-69
Human and animal findings indicate that males and females display major differences in risk for and consequences of alcohol abuse and alcoholism. These differences are in large part mediated by sex-specific hormonal environments. Gonadal and adrenal secretory products are known to modulate the neurobehavioral responses of ethanol (EtOH) dependence and withdrawal. However, the effects of these steroids on physiological adaptations, such as thermoregulation, are less well established. To study the role of sex-related hormones in mediating sex differences in the hypothermic response to acute challenge with EtOH, we compared the EtOH-induced hypothermic responses of EtOH-naïve male and female rats and EtOH-dependent (on the third day of withdrawal) male and female rats before (intact) and after depletion of all gonadal and adrenal steroids by gonadectomy (GDX) with or without adrenalectomy (ADX).Intact and GDX male and female rats, with or without ADX, were fed an EtOH-containing liquid diet for 15 days while control (EtOH-naïve) rats were pairfed the isocaloric liquid diet without EtOH or fed normal rat chow and water. On the third day of withdrawal from the EtOH diet we tested the hypothermic response to EtOH challenge (1.5 g/kg BWt, ip). Blood alcohol content (BAC) and corticosterone (CORT) content were analyzed in a separate series of intact and GDX males and females with and without ADX in response to the EtOH challenge.Ethanol-induced hypothermia was significantly greater and its duration significantly longer in intact males than females when subjects were EtOH-naïve. EtOH-induced hypothermia was significantly greater in intact females than males by the third day of withdrawal from EtOH dependence. GDX in males significantly shortened the duration of the hypothermic response and tended to blunt EtOH-induced hypothermia while response duration was significantly extended by GDX in females that tended to enhance EtOH-hypothermia. EtOH-induced hypothermia was significantly enhanced and its duration significantly lengthened by combined GDX and ADX in EtOH-naïve and -withdrawn males and by combined GDX and ADX in EtOH-naïve but not EtOH-withdrawn females. These differential EtOH-induced hypothermic responses did not appear to be caused by differences in EtOH handling among the groups. The absence of adrenal activation by EtOH in the GDX-ADX males and females contributes to their enhanced EtOH-induced hypothermic responses.These results implicate the direct and indirect effects of removal of gonadal and adrenal secretory products as mediators of the thermoregulatory actions of EtOH.
View details for DOI 10.1111/j.1530-0277.2008.00811.x
View details for Web of Science ID 000261960600007
View details for PubMedID 18945222
Lasting neuroendocrine-immune effects of traumatic brain injury in rats
JOURNAL OF NEUROTRAUMA
2006; 23 (12): 1802-1813
Traumatic brain injury (TBI) is a principal cause of long-term physical, cognitive, behavioral, and social deficits in young adults, which frequently coexist with a high incidence of substance abuse disorders. However, few studies have examined the long-term effects of TBI on the neuroendocrine-immune system. TBI was induced in adult male rats under isoflurane anesthesia by cortical contusion injury with a pneumatic piston positioned stereotaxically over the left parietal cortex. Controls underwent sham surgery without injury. At 4 weeks post-injury, the plasma corticosterone response to 30-min restraint stress was significantly blunted in TBI rats compared to the sham controls. One week later, transmitters were implanted for continuous biotelemetric recording of body temperature and spontaneous locomotor activity. At 6 weeks post-injury, the febrile response to i.p. injection of the bacterial endotoxin, lipopolysaccharide (LPS; 50 microg/kg), was significantly lower in TBI than in sham rats. At 8 weeks, swimming in the forced swim test was significantly less in TBI than sham rats. At 9 weeks, rats were rendered ethanol (EtOH) dependent by feeding an EtOH-containing liquid diet for 14 days. Cosine rhythmometry analysis of circadian body temperature Midline Estimating Statistic of Rhythm (MESOR), amplitudes, and acrophases indicated differential effects of EtOH and withdrawal in the two groups. Light- and dark-phase activity analysis indicated that TBI rats were significantly more active than the sham group, and that EtOH and withdrawal differentially affected their activity. Given the extensive interactions of the neuroendocrine-immune systems, these results demonstrate that TBI produces lasting dysregulation amidst the central substrates for allostasis and circadian rhythmicity.
View details for Web of Science ID 000243056100008
View details for PubMedID 17184190
Differential effects of alcohol consumption and withdrawal on circadian temperature and activity rhythms in Sprague-Dawley, Lewis, and Fischer male and female rats
ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH
2006; 30 (3): 438–47
Hypothalamic synthesis and secretion of corticotropin-releasing hormone (CRH), a putative mediator of various behavioral and physiological responses to ethanol (EtOH), is defective in inbred Lewis (LEW) rats in comparison with their genetically related inbred Fischer 344 (F344) and outbred Sprague-Dawley (S-D) strains. We aimed to characterize the effects of continuous EtOH consumption and withdrawal on circadian patterns of body temperature and spontaneous locomotor activity in males and females of these 3 strains.Adult LEW, F344, and S-D males and randomly cycling females were fed an EtOH-containing liquid diet or the control (pair-fed or lab chow and water) diet for 14 days. Biotelemetric body temperature data for the last 3 days of EtOH diet feeding and the first 3 days of withdrawal were subjected to cosinor analysis of the circadian rhythm parameters of midline-estimating statistic of rhythm (MESOR), amplitude, and acrophase. Mean dark-phase activity during these periods was also computed.In the control diet condition, the MESORs and amplitudes of LEW males were lower than those of F344 males. MESORs of rhythms of LEW females were lower than those of both F344 and S-D females. Ethanol consumption caused hypothermia with reduced MESORs and amplitudes of LEW and F344 males and amplitudes of F344 and S-D females. Upon withdrawal, MESORs of the males increased during each day as the amplitudes decreased, reflective of their initial withdrawal-induced dark-phase hypothermia, which was most pronounced in the LEW males, followed by light-phase hyperthermia. MESORs of females were not affected by withdrawal; their amplitudes were differentially affected. Acrophase of LEW males shifted from dark to light on the first day of withdrawal. All rats responded to EtOH exposure with a reduction of dark-phase spontaneous locomotor activity and an immediate increase upon withdrawal.Body temperature rhythms of the males were generally more affected by EtOH consumption and withdrawal than the females; within each sex, LEW and F344 rats differed significantly. The specific hormonal factors that mediate the differential temperature responses remain to be defined.
View details for DOI 10.1111/j.1530-0277.2006.00048.x
View details for Web of Science ID 000235817300006
View details for PubMedID 16499484