Dan R Littman

CUNY Graduate Center, New York, New York, United States

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Publications (326)4860.61 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: The role of the microenvironment in T cell acute lymphoblastic leukemia (T-ALL), or any acute leukemia, is poorly understood. Here we demonstrate that T-ALL cells are in direct, stable contact with CXCL12-producing bone marrow stroma. Cxcl12 deletion from vascular endothelial, but not perivascular, cells impeded tumor growth, suggesting a vascular niche for T-ALL. Moreover, genetic targeting of Cxcr4 in murine T-ALL after disease onset led to rapid, sustained disease remission, and CXCR4 antagonism suppressed human T-ALL in primary xenografts. Loss of CXCR4 targeted key T-ALL regulators, including the MYC pathway, and decreased leukemia initiating cell activity in vivo. Our data identify a T-ALL niche and suggest targeting CXCL12/CXCR4 signaling as a powerful therapeutic approach for T-ALL. Copyright © 2015 Elsevier Inc. All rights reserved.
    Cancer cell 06/2015; 27(6):755-768. DOI:10.1016/j.ccell.2015.05.002 · 23.89 Impact Factor
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    ABSTRACT: During development, progenitor cells with binary potential give rise to daughter cells that have distinct functions. Heritable epigenetic mechanisms then lock in gene-expression programs that define lineage identity. Regulation of the gene encoding the T cell-specific coreceptor CD4 in helper and cytotoxic T cells exemplifies this process, with enhancer- and silencer-regulated establishment of epigenetic memory for stable gene expression and repression, respectively. Using a genetic screen, we identified the DNA-methylation machinery as essential for maintaining silencing of Cd4 in the cytotoxic lineage. Furthermore, we found a requirement for the proximal enhancer in mediating the removal of DNA-methylation marks from Cd4, which allowed stable expression of Cd4 in helper T cells. Our findings suggest that stage-specific methylation and demethylation events in Cd4 regulate its heritable expression in response to the distinct signals that dictate lineage 'choice' during T cell development.
    Nature Immunology 06/2015; DOI:10.1038/ni.3198 · 24.97 Impact Factor
  • Randy S Longman · Dan R Littman
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    ABSTRACT: This review will highlight recent advances functionally linking the gut microbiome with mucosal and systemic immune cell activation underlying autoimmunity. Dynamic interactions between the gut microbiome and environmental cues (including diet and medicines) shape the effector potential of the microbial organ. Key bacteria and viruses have emerged that, in defined microenvironments, play a critical role in regulating effector lymphocyte functions. The coordinated interactions between these different microbial kingdoms - including bacteria, helminths, and viruses (termed transkingdom interactions) - play a key role in shaping immunity. Emerging strategies to identify immunologically relevant microbes with the potential to regulate immune cell functions both at mucosal sites and systemically will likely define diagnostic and therapeutic targets. The microbiome constitutes a critical microbial organ with coordinated interactions that shape host immunity.
    Current opinion in rheumatology 05/2015; 27(4). DOI:10.1097/BOR.0000000000000190 · 5.07 Impact Factor
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    Journal of Experimental Medicine 05/2015; 212(6). DOI:10.1084/jem.2013237805062015c · 13.91 Impact Factor
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    ABSTRACT: 16S-ribosomal sequencing and other metagonomic techniques provide snapshots of microbial communities, revealing phylogeny and the abundances of microbial populations across diverse ecosystems. While changes in microbial community structure are demonstrably associated with certain environmental conditions, identification of underlying mechanisms requires new statistical tools, as these datasets present several technical challenges. First, the abundances of microbial operational taxonomic units (OTUs) from 16S datasets are compositional, and thus, microbial abundances are not independent. Secondly, microbial sequencing-based studies typically measure hundreds of OTUs on only tens to hundreds of samples; thus, inference of OTU-OTU interaction networks is severely under-powered, and additional assumptions are required for accurate inference. Here, we present SPIEC-EASI (SParse InversE Covariance Estimation for Ecological Association Inference), a statistical method for the inference of microbial ecological interactions from metagenomic datasets that addresses both of these issues. SPIEC-EASI combines data transformations developed for compositional data analysis with a graphical model inference framework that assumes the underlying ecological interaction network is sparse. To reconstruct the interaction network, SPIEC-EASI relies on algorithms for sparse neighborhood and inverse covariance selection. Because no large-scale microbial ecological networks have been experimentally validated, SPIEC-EASI comprises computational tools to generate realistic OTU count data from a set of diverse underlying network topologies. SPIEC-EASI outperforms state-of-the-art methods in terms of edge recovery and network properties on realistic synthetic data under a variety of scenarios. SPIEC-EASI also reproducibly predicts previously unknown microbial interactions using data from the American Gut project.
    PLoS Computational Biology 05/2015; 11(5):e1004226. DOI:10.1371/journal.pcbi.1004226 · 4.83 Impact Factor
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    ABSTRACT: The balance of effector and regulatory T cell function, dependent on multiple signals and epigenetic regulators, is critical to immune self-tolerance. Dysregulation of T helper 17 (Th17) effector cells is associated with multiple autoimmune diseases, including multiple sclerosis. Here, we report that Sirtuin 1 (SIRT1), a protein deacetylase previously reported to have an antiinflammatory function, in fact promotes autoimmunity by deacetylating RORγt, the signature transcription factor of Th17 cells. SIRT1 increases RORγt transcriptional activity, enhancing Th17 cell generation and function. Both T cell-specific Sirt1 deletion and treatment with pharmacologic SIRT1 inhibitors suppress Th17 differentiation and are protective in a mouse model of multiple sclerosis. Moreover, analysis of infiltrating cell populations during disease induction in mixed hematopoietic chimeras shows a marked bias against Sirt1-deficient Th17 cells. These findings reveal an unexpected proinflammatory role of SIRT1 and, importantly, support the possible therapeutic use of SIRT1 inhibitors against autoimmunity. © 2015 Lim et al.
    Journal of Experimental Medicine 04/2015; 212(5). DOI:10.1084/jem.20132378 · 13.91 Impact Factor
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    ABSTRACT: Mice deficient in the nuclear hormone receptor RORγt have defective development of thymocytes, lymphoid organs, Th17 cells, and type 3 innate lymphoid cells. RORγt binds to oxysterols derived from cholesterol catabolism, but it is not clear whether these are its natural ligands. Here, we show that sterol lipids are necessary and sufficient to drive RORγt-dependent transcription. We combined overexpression, RNAi, and genetic deletion of metabolic enzymes to study RORγ-dependent transcription. Our results are consistent with the RORγt ligand(s) being a cholesterol biosynthetic intermediate (CBI) downstream of lanosterol and upstream of zymosterol. Analysis of lipids bound to RORγ identified molecules with molecular weights consistent with CBIs. Furthermore, CBIs stabilized the RORγ ligand-binding domain and induced coactivator recruitment. Genetic deletion of metabolic enzymes upstream of the RORγt-ligand(s) affected the development of lymph nodes and Th17 cells. Our data suggest that CBIs play a role in lymphocyte development potentially through regulation of RORγt.
    Cell metabolism 02/2015; 21(2):286-297. DOI:10.1016/j.cmet.2015.01.004 · 16.75 Impact Factor
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    ABSTRACT: Objective: To characterize the diversity and taxonomic relative abundance of the gut microbiota in patients with never-treated, recent-onset psoriatic arthritis (PsA). Methods: High-throughput 16S rRNA pyrosequencing was utilized to compare community composition of gut microbiota in PsA patients (n=16), subjects with psoriasis of the skin (Ps) (n=15) and healthy, matched-controls (n=17). Samples were further assessed for the presence and levels of fecal and serum secretory immunoglobulin A (sIgA), pro-inflammatory proteins and fatty-acids. Results: The gut microbiota observed in PsA and Ps patients was less diverse when compared to healthy controls. These could be attributed to the reduced presence of several taxa. While both groups showed a relative decrease in Coprococcus spp., PsA samples were characterized by a significant reduction in Akkermansia, Ruminococcus, and Pseudobutyrivibrio. Supernatants of fecal samples from PsA patients revealed an increase in sIgA and a decrease in receptor activator of nuclear factor kappa-B ligand (RANKL) levels. Fatty acid analysis revealed low levels of hexanoate and heptanoate in PsA and Ps patients. Conclusion: PsA and Ps patients had a lower relative abundance of multiple intestinal bacteria. Although some genera were concomitantly decreased in both conditions, PsA samples had lower abundance of reportedly beneficial taxa. This gut microbiota profile in PsA was similar to that published for patients with IBD and was associated with changes in specific inflammatory proteins unique to this group, and distinct from Ps and controls. Thus, the role of gut microbiota in the continuum of Ps-PsA pathogenesis and the associated immune response merits further study. © 2014 American College of Rheumatology.
    Arthritis and Rheumatology 10/2014; 67(1). DOI:10.1002/art.38892
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    ABSTRACT: Interleukin (IL)-22-producing group 3 innate lymphoid cells (ILC3) promote mucosal healing and maintain barrier integrity, but how microbial signals are integrated to regulate mucosal protection offered by these cells remains unclear. Here, we show that in vivo depletion of CX3CR1(+) mononuclear phagocytes (MNPs) resulted in more severe colitis and death after infection with Citrobacter rodentium. This phenotype was rescued by exogenous IL-22, which was endogenously produced by ILC3 in close spatial proximity to CX3CR1(+) MNPs that were dependent on MyD88 signaling. CX3CR1(+) MNPs from both mouse and human tissue produced more IL-23 and IL-1β than conventional CD103(+) dendritic cells (cDCs) and were more efficient than cDCs in supporting IL-22 production in ILC3 in vitro and in vivo. Further, colonic ILC3 from patients with mild to moderate ulcerative colitis or Crohn's disease had increased IL-22 production. IBD-associated SNP gene set analysis revealed enrichment for genes selectively expressed in human intestinal MNPs. The product of one of these, TL1A, potently enhanced IL-23- and IL-1β-induced production of IL-22 and GM-CSF by ILC3. Collectively, these results reveal a critical role for CX3CR1(+) mononuclear phagocytes in integrating microbial signals to regulate colonic ILC3 function in IBD.
    Journal of Experimental Medicine 07/2014; 211(8). DOI:10.1084/jem.20140678 · 13.91 Impact Factor
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    ABSTRACT: The vertebrate intestinal tract is colonized by hundreds of species of bacteria that must be compartmentalized and tolerated to prevent invasive growth and harmful inflammatory responses. Signaling initiated by commensal bacteria shapes antigen-specific mucosal and systemic adaptive immunity. A distinct type of effector CD4(+) T cells, Th17 cells, have a key role in coordinating the inflammatory immune responses that afford protection to pathogens at the mucosal interface. Balancing this powerful inflammatory response, regulatory T cells limit collateral damage and provide antigen-specific tolerance to both food and microbial antigens. Here, we discuss the implications for how the microbiota as a whole contributes to compartmentalization from the host and how individual constituents of the microbiota influence the functions and repertoire of effector T cells and organ-specific autoimmune disease.
    Cold Spring Harbor Symposia on Quantitative Biology 06/2014; 78(1). DOI:10.1101/sqb.2013.78.020081
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    ABSTRACT: T-helper-17 (TH17) cells have critical roles in mucosal defence and in autoimmune disease pathogenesis. They are most abundant in the small intestine lamina propria, where their presence requires colonization of mice with microbiota. Segmented filamentous bacteria (SFB) are sufficient to induce TH17 cells and to promote TH17-dependent autoimmune disease in animal models. However, the specificity of TH17 cells, the mechanism of their induction by distinct bacteria, and the means by which they foster tissue-specific inflammation remain unknown. Here we show that the T-cell antigen receptor (TCR) repertoire of intestinal TH17 cells in SFB-colonized mice has minimal overlap with that of other intestinal CD4(+) T cells and that most TH17 cells, but not other T cells, recognize antigens encoded by SFB. T cells with antigen receptors specific for SFB-encoded peptides differentiated into RORγt-expressing TH17 cells, even if SFB-colonized mice also harboured a strong TH1 cell inducer, Listeria monocytogenes, in their intestine. The match of T-cell effector function with antigen specificity is thus determined by the type of bacteria that produce the antigen. These findings have significant implications for understanding how commensal microbiota contribute to organ-specific autoimmunity and for developing novel mucosal vaccines.
    Nature 04/2014; 510(7503). DOI:10.1038/nature13279 · 42.35 Impact Factor
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    ABSTRACT: The impact of nutritional status during fetal life on the overall health of adults has been recognized; however, dietary effects on the developing immune system are largely unknown. Development of secondary lymphoid organs occurs during embryogenesis and is considered to be developmentally programmed. Secondary lymphoid organ formation depends on a subset of type 3 innate lymphoid cells (ILC3) named lymphoid tissue inducer (LTi) cells. Here we show that mouse fetal ILC3s are controlled by cell-autonomous retinoic acid (RA) signalling in utero, which pre-sets the immune fitness in adulthood. We found that embryonic lymphoid organs contain ILC progenitors that differentiate locally into mature LTi cells. Local LTi cell differentiation was controlled by maternal retinoid intake and fetal RA signalling acting in a haematopoietic cell-autonomous manner. RA controlled LTi cell maturation upstream of the transcription factor RORγt. Accordingly, enforced expression of Rorgt restored maturation of LTi cells with impaired RA signalling, whereas RA receptors directly regulated the Rorgt locus. Finally, we established that maternal levels of dietary retinoids control the size of secondary lymphoid organs and the efficiency of immune responses in the adult offspring. Our results reveal a molecular link between maternal nutrients and the formation of immune structures required for resistance to infection in the offspring.
    Nature 03/2014; 508(7494). DOI:10.1038/nature13158 · 42.35 Impact Factor
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    ABSTRACT: Microglia are the resident macrophages of the CNS, and their functions have been extensively studied in various brain pathologies. The physiological roles of microglia in brain plasticity and function, however, remain unclear. To address this question, we generated CX3CR1(CreER) mice expressing tamoxifen-inducible Cre recombinase that allow for specific manipulation of gene function in microglia. Using CX3CR1(CreER) to drive diphtheria toxin receptor expression in microglia, we found that microglia could be specifically depleted from the brain upon diphtheria toxin administration. Mice depleted of microglia showed deficits in multiple learning tasks and a significant reduction in motor-learning-dependent synapse formation. Furthermore, Cre-dependent removal of brain-derived neurotrophic factor (BDNF) from microglia largely recapitulated the effects of microglia depletion. Microglial BDNF increases neuronal tropomyosin-related kinase receptor B phosphorylation, a key mediator of synaptic plasticity. Together, our findings reveal that microglia serve important physiological functions in learning and memory by promoting learning-related synapse formation through BDNF signaling.
    Cell 12/2013; 155(7):1596-609. DOI:10.1016/j.cell.2013.11.030 · 33.12 Impact Factor
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    ABSTRACT: Immunoglobulin A (IgA) production at mucosal surfaces contributes to protection against pathogens and controls intestinal microbiota composition. However, mechanisms regulating IgA induction are not completely defined. We show that soluble lymphotoxin α (sLTα3) produced by RORγt(+) innate lymphoid cells (ILCs) controls T cell-dependent IgA induction in the lamina propria via regulation of T cell homing to the gut. By contrast, membrane-bound lymphotoxin β (LTα1β2) produced by RORγt(+) ILCs is critical for T cell-independent IgA induction in the lamina propria via control of dendritic cell functions. Ablation of LTα in RORγt(+) cells abrogated IgA production in the gut and altered microbiota composition. Thus, soluble and membrane-bound lymphotoxins produced by ILCs distinctly organize adaptive immune responses in the gut and control commensal microbiota composition.
    Science 12/2013; 342(6163):1243-6. DOI:10.1126/science.1243364 · 31.48 Impact Factor
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    ABSTRACT: Rheumatoid arthritis (RA) is a prevalent systemic autoimmune disease, caused by a combination of genetic and environmental factors. Animal models suggest a role for intestinal bacteria in supporting the systemic immune response required for joint inflammation. Here we performed 16S sequencing on 114 stool samples from rheumatoid arthritis patients and controls, and shotgun sequencing on a subset of 44 such samples. We identified the presence of Prevotella copri as strongly correlated with disease in new-onset untreated rheumatoid arthritis (NORA) patients. Increases in Prevotella abundance correlated with a reduction in Bacteroides and a loss of reportedly beneficial microbes in NORA subjects. We also identified unique Prevotella genes that correlated with disease. Further, colonization of mice revealed the ability of P. copri to dominate the intestinal microbiota and resulted in an increased sensitivity to chemically induced colitis. This work identifies a potential role for P. copri in the pathogenesis of RA. DOI: http://dx.doi.org/10.7554/eLife.01202.001
    eLife Sciences 11/2013; 2. DOI:10.7554/eLife.01202 · 8.52 Impact Factor
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    ABSTRACT: Mice cannot be used to evaluate HIV-1 therapeutics and vaccines because they are not infectible by HIV-1 due to structural differences between several human and mouse proteins required for HIV-1 entry and replication including CD4, CCR5 and cyclin T1. We overcame this limitation by constructing mice with CD4 enhancer/promoter-regulated human CD4, CCR5 and cyclin T1 genes integrated as tightly linked transgenes (hCD4/R5/cT1 mice) promoting their efficient co-transmission and enabling the murine CD4-expressing cells to support HIV-1 entry and Tat-mediated LTR transcription. All of the hCD4/R5/cT1 mice developed disseminated infection of tissues that included the spleen, small intestine, lymph nodes and lungs after intravenous injection with an HIV-1 infectious molecular clone (HIV-IMC) expressing Renilla reniformis luciferase (LucR). Furthermore, localized infection of cervical-vaginal mucosal leukocytes developed after intravaginal inoculation of hCD4/R5/cT1 mice with the LucR-expressing HIV-IMC. hCD4/R5/cT1 mice reproducibly developed in vivo infection after inoculation with LucR-expressing HIV-IMC which could be bioluminescently quantified and visualized with a high sensitivity and specificity which enabled them to be used to evaluate the efficacy of HIV-1 therapeutics. Treatment with highly active anti-retroviral therapy or one dose of VRC01, a broadly neutralizing anti-HIV-1 antibody, almost completed inhibited acute systemic HIV-1 infection of the hCD4/R5/cT1 mice. hCD4/R5/cT1 mice could also be used to evaluate the capacity of therapies delivered by gene therapy to inhibit in vivo HIV infection. VRC01 secreted in vivo by primary B cells transduced with a VRC01-encoding lentivirus transplanted into hCD4/R5/cT1 mice markedly inhibited infection after intravenous challenge with LucR-expressing HIV-IMC. The reproducible infection of CD4/R5/cT1 mice with LucR-expressing HIV-IMC after intravenous or mucosal inoculation combined with the availability of LucR-expressing HIV-IMC expressing transmitted/founder and clade A/E and C Envs will provide researchers with a highly accessible pre-clinical in vivo HIV-1-infection model to study HIV-1 acquisition, treatment, and prevention.
    PLoS ONE 05/2013; 8(5):e63537. DOI:10.1371/journal.pone.0063537 · 3.23 Impact Factor
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    ABSTRACT: Lymphocyte homing, which contributes to inflammation, has been studied extensively in the small intestine, but there is little known about homing to the large intestine, the site most commonly affected in inflammatory bowel disease. GPR15, an orphan G protein-coupled receptor, controlled the specific homing of T cells, particularly FOXP3(+) regulatory T cells (Tregs), to the large intestine lamina propria (LILP). GPR15 expression was modulated by gut microbiota and transforming growth factor-β1, but not by retinoic acid. GPR15-deficient mice were prone to develop more severe large intestine inflammation, which was rescued by the transfer of GPR15-sufficient Tregs. Our findings thus describe a T cell homing receptor for LILP and indicate that GPR15 plays a role in mucosal immune tolerance largely by regulating the influx of Tregs.
    Science 05/2013; DOI:10.1126/science.1237013 · 31.48 Impact Factor
  • Gastroenterology 05/2013; 144(5):S-7. DOI:10.1016/S0016-5085(13)60019-0 · 13.93 Impact Factor
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    ABSTRACT: CD4(+) T cells can perform a panoply of tasks to shape an effective response against a pathogen. Limited attention has been paid to the potential importance of functional CD4(+) T cell responses in the context of the development of next-generation vaccines, including HIV vaccines. Many CD4(+) T cell functions are newly appreciated and only partially understood. A workshop was held as a forum to bring together a small group of experts to exchange ideas on the role of CD4(+) T cells in developing durable functional antibody responses, via follicular helper T cells, as well as on the roles of CD4(+) T cells in other aspects of protective immunity. Here we discuss whether CD4(+) T cell responses may represent a beneficial component of an efficacious HIV vaccine.
    Nature medicine 02/2013; 19(2):143-9. DOI:10.1038/nm.3054 · 28.05 Impact Factor

Publication Stats

57k Citations
4,860.61 Total Impact Points


  • 1998–2015
    • CUNY Graduate Center
      New York, New York, United States
    • New York University
      New York City, New York, United States
  • 1997–2015
    • NYU Langone Medical Center
      • Skirball Institute of Biomolecular Medicine
      New York, New York, United States
    • San Raffaele Scientific Institute
      Milano, Lombardy, Italy
  • 2014
    • Erasmus MC
      • Department of Cell Biology
      Rotterdam, South Holland, Netherlands
  • 1985–2014
    • Howard Hughes Medical Institute
      Ashburn, Virginia, United States
  • 2012
    • University of North Carolina at Chapel Hill
      • Lineberger Comprehensive Cancer Center
      Chapel Hill, NC, United States
    • Albert Einstein College of Medicine
      New York, New York, United States
    • Indiana University South Bend
      South Bend, Indiana, United States
  • 2010
    • Christian-Albrechts-Universität zu Kiel
      Kiel, Schleswig-Holstein, Germany
  • 2008
    • Yale University
      New Haven, Connecticut, United States
  • 1988–2006
    • University of California, San Francisco
      • Department of Microbiology and Immunology
      San Francisco, CA, United States
  • 2004
    • University of Texas MD Anderson Cancer Center
      Houston, Texas, United States
  • 2001
    • University of Pennsylvania
      Filadelfia, Pennsylvania, United States
  • 2000
    • National Institute of Allergy and Infectious Diseases
      • Laboratory of Parasitic Diseases (LPD)
      Maryland, United States
  • 1999
    • Memorial Sloan-Kettering Cancer Center
      New York, New York, United States
  • 1995
    • French National Centre for Scientific Research
      Lutetia Parisorum, Île-de-France, France
  • 1994
    • The Scripps Research Institute
      La Jolla, California, United States
  • 1990
    • University of Washington Seattle
      • Department of Biochemistry
      Seattle, Washington, United States
  • 1987–1988
    • Stanford University
      • Department of Medicine
      Palo Alto, California, United States
    • Harvard University
      Cambridge, Massachusetts, United States
  • 1986
    • Wistar Institute
      Philadelphia, Pennsylvania, United States