About

Dan R. Littman is a professor in the Department of Cell Biology and holds the Helen L. and Martin S. Kimmel Professorship of Molecular Immunology at NYU Grossman School of Medicine. His research focuses on the molecular mechanisms involved in the specification of distinct T lymphocyte lineages during development in the thymus and in response to microbial challenges in peripheral tissues. His laboratory studies how thymocytes are specified to differentiate towards helper or cytotoxic lineages, characterizing transcription factors and epigenetic programs involved in lineage specification. Additionally, his work on peripheral T cells has led to the identification of the nuclear receptor RORgt, which is essential for the differentiation of Th17 cells, critical in mucosal defense and inflammatory diseases. Littman's research investigates how commensal microbes influence T cell differentiation, including regulatory T cells, and how these interactions can trigger systemic autoimmune diseases. His studies extend to understanding microbiota-immune system communication, the influence of microbial products on systemic immune responses, and the mechanisms of HIV pathogenesis, aiming to develop new therapies and vaccines.

Research topics

• Biology
• Biochemistry
• Cell biology
• Medicine
• Immunology
• Bioinformatics
• Microbiology

Selected publications

• C10ORF99 (GPR15L) increases susceptibility to colitis and colitis-induced colorectal cancer via GPR15-independent mechanisms, while mediating GPR15-dependent T cell migration to the large intestine

  Mucosal Immunology · 2025-08-13

  articleOpen access

  GPR15 is a homing receptor important for T cell migration to the large intestine, the primary site of inflammation in ulcerative colitis. Both GPR15 and its ligand, C10ORF99, represent potential therapeutic targets for the treatment of IBD; however, the roles of C10ORF99 in the large intestine are not fully elucidated. Here, we demonstrate that C10ORF99 is the non-redundant ligand of GPR15 mediating T cell migration to the large intestine. Furthermore, we demonstrate that C10ORF99 has GPR15-independent functions in the large intestine: C10ORF99 deficiency is protective in chemically induced colitis, and this appears to result from enhanced epithelial barrier regeneration. We found that C10ORF99 can inhibit intestinal epithelial proliferation in a cell-intrinsic manner. Additionally, due to this protection from colitis development in the absence of C10ORF99, C10ORF99 KO is also protected from colitis-associated colorectal cancer development. These data indicate that the deficiency of C10ORF99 can not only block pathogenic T cell migration to the large intestine, but can also promote epithelial barrier repair, potentially offering additional advantages for recovery from ulcerative colitis.

  PublisherDOI

• Disease tolerant mice shelter a pathogenic intestinal microbiota able to trigger lethal disease in low tolerant hosts

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-02-26 · 1 citations

  preprintOpen access

  Abstract Disease tolerance is a defensive strategy that limits tissue damage during infection. Macrophage migration inhibitory factor (MIF)-deficient mice ( Mif -/- ) are protected in different models of infection and intestinal inflammation due to unclear disease tolerance mechanisms, whereas low disease-tolerant Il10 -/- mice develop microbiota-dependent spontaneous gut inflammation. Here, we examined whether IL-10 is required for the phenotype seen in Mif -/- mice and, conversely, the contribution of MIF during IL-10 deficiency. While breeding for double-deficient Mif -/- Il10 -/- mice, we unexpectedly observed that Il10 -/- individuals died within days after co-housing with Mif -/- mice. We found that healthy Mif -/- hosts endure a highly diverse, unique and dysbiotic-like microbiota composition, including antibiotic-resistant Enterobacteriaceae species, which were sufficient to cause acute and lethal Th1-driven colitis in Il10 -/- recipients. The disease was characterized by increased frequencies of IFNγ + cells and neutrophils within colonic lamina propria. Mif -/- Il10 -/- mice died prematurely, and survivors developed communicable disease, - indicating that lack of IL-10 is a dominant trait. These findings suggest that tolerant individuals harbor a gut microbiota enriched in pathogens/pathobionts, which can trigger disease in susceptible hosts.

  PublisherOA PDFDOI

• A Validated Regulatory Network for Th17 Cell Specification

  Cell · 2025-09-24

  erratumSenior author
  PublisherDOI

• Addendum: Unravelling cysteine-deficiency-associated rapid weight loss

  Nature · 2025-06-26

  articleOpen access

  similarly reports a 30% weight loss upon cysteine restriction in a Cse knockout mouse model.Like our findings, they observe depletion of CoA and GSH, strong induction of FGF21, comparable changes in adipose tissue and increased lipid utilization.Furthermore, Lee et al.'s study provides detailed mechanistic insights into adipose tissue changes, including rapid browning, metabolic shifts and signaling pathways driving these processes.This complements our work focused on the biochemical aspects of cysteine depletion by adding valuable details on the physiological responses.In summary, the combined findings from both studies significantly enhance our understanding of the effects of cysteine depletion and its role in driving rapid weight loss.

  PublisherOA PDFDOI

• Inflammatory disease microbiomes share a functional pathogenicity predicted by C-reactive protein

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-01-18

  preprintOpen access

  We examine disease-specific and cross-disease functions of the human gut microbiome by colonizing germ-free mice, at risk for inflammatory arthritis, colitis, or neuroinflammation, with over 100 human fecal microbiomes from subjects with rheumatoid arthritis, ankylosing spondylitis, multiple sclerosis, ulcerative colitis, Crohn's disease, or colorectal cancer. We find common inflammatory phenotypes driven by microbiomes from individuals with intestinal inflammation or inflammatory arthritis, as well as distinct functions specific to microbiomes from multiple sclerosis patients. Inflammatory disease in mice colonized with human microbiomes correlated with systemic inflammation, measured by C-reactive protein, in the human donors. These cross-disease patterns of human microbiome pathogenicity mirror features of the inflammatory diseases, including therapeutic targets and the presence or absence of systemic inflammation, suggesting shared and disease-specific mechanisms by which the microbiome is shaped and drives pathogenic inflammatory responses.

  PublisherOA PDFDOI

• Niche-specific dermal macrophage loss promotes skin capillary ageing

  Nature · 2025-10-15 · 9 citations

  articleOpen accessSenior authorCorresponding

  Abstract All mammalian organs depend on resident macrophage populations to coordinate repair and facilitate tissue-specific functions 1–3 . Functionally distinct macrophage populations reside in discrete tissue niches and are replenished through a combination of local proliferation and monocyte recruitment 4,5 . Declines in macrophage abundance and function have been linked to age-associated pathologies, including atherosclerosis, cancer and neurodegeneration 6–8 . However, the mechanisms that coordinate macrophage organization and replenishment within ageing tissues remain largely unclear. Here we show that capillary-associated macrophages (CAMs) are selectively lost over time, contributing to impaired vascular repair and reduced tissue perfusion in older mice. To investigate resident macrophage behaviour in vivo, we used intravital two-photon microscopy in live mice to non-invasively image the skin capillary plexus, a spatially well-defined vascular niche that undergoes rarefication and functional decline with age. We find that CAMs are lost at a rate exceeding capillary loss, resulting in macrophage-deficient vascular niches in both mice and humans. CAM phagocytic activity was locally required to repair obstructed capillary blood flow, leaving macrophage-deficient niches selectively vulnerable under homeostatic and injury conditions. Our study demonstrates that homeostatic renewal of resident macrophages is less precisely regulated than previously suggested 9–11 . Specifically, neighbouring macrophages do not proliferate or reorganize to compensate for macrophage loss without injury or increased growth factors, such as colony-stimulating factor 1 (CSF1). These limitations in macrophage renewal may represent early and targetable contributors to tissue ageing.

  PublisherDOI

• Unravelling cysteine-deficiency-associated rapid weight loss

  Nature · 2025-05-21 · 33 citations

  articleOpen access

  Abstract Around 40% of the US population and 1 in 6 individuals worldwide have obesity, with the incidence surging globally 1,2 . Various dietary interventions, including carbohydrate, fat and, more recently, amino acid restriction, have been explored to combat this epidemic 3–6 . Here we investigated the impact of removing individual amino acids on the weight profiles of mice. We show that conditional cysteine restriction resulted in the most substantial weight loss when compared to essential amino acid restriction, amounting to 30% within 1 week, which was readily reversed. We found that cysteine deficiency activated the integrated stress response and oxidative stress response, which amplify each other, leading to the induction of GDF15 and FGF21, partly explaining the phenotype 7–9 . Notably, we observed lower levels of tissue coenzyme A (CoA), which has been considered to be extremely stable 10 , resulting in reduced mitochondrial functionality and metabolic rewiring. This results in energetically inefficient anaerobic glycolysis and defective tricarboxylic acid cycle, with sustained urinary excretion of pyruvate, orotate, citrate, α-ketoglutarate, nitrogen-rich compounds and amino acids. In summary, our investigation reveals that cysteine restriction, by depleting GSH and CoA, exerts a maximal impact on weight loss, metabolism and stress signalling compared with other amino acid restrictions. These findings suggest strategies for addressing a range of metabolic diseases and the growing obesity crisis.

  PublisherOA PDFDOI

• PRDM16-dependent antigen-presenting cells induce tolerance to gut antigens

  Nature · 2025-04-14 · 52 citations

  articleOpen accessSenior author

  Abstract The gastrointestinal tract is continuously exposed to foreign antigens in food and commensal microorganisms with potential to induce adaptive immune responses. Peripherally induced T regulatory (pT reg ) cells are essential for mitigating inflammatory responses to these agents 1–4 . Although RORγt + antigen-presenting cells (APCs) have been shown to programme gut microbiota-specific pT reg cells 5–7 , their definition remains incomplete, and the APC responsible for food tolerance has remained unknown. Here we identify an APC subset that is required for differentiation of both food- and microbiota-specific pT reg cells and for establishment of oral tolerance. Development and function of these APCs require expression of the transcription factors PRDM16 and RORγt, as well as a unique Rorc(t) cis -regulatory element. Gene expression, chromatin accessibility, and surface marker analysis establish the pT reg -inducing APCs as myeloid in origin, distinct from type 3 innate lymphoid cells, and sharing epigenetic profiles with classical dendritic cells, and designate them PRDM16 + RORγt + tolerizing dendritic cells (tolDCs). Upon genetic perturbation of tolDCs, we observe a substantial increase in food antigen-specific T helper 2 cells in lieu of pT reg cells, leading to compromised tolerance in mouse models of asthma and food allergy. Single-cell analyses of freshly resected mesenteric lymph nodes from a human organ donor, as well as multiple specimens of human intestine and tonsil, reveal candidate tolDCs with co-expression of PRDM16 and RORC and an extensive transcriptome shared with tolDCs from mice, highlighting an evolutionarily conserved role across species. Our findings suggest that a better understanding of how tolDCs develop and how they regulate T cell responses to food and microbial antigens could offer new insights into developing therapeutic strategies for autoimmune and allergic diseases as well as organ transplant tolerance.

  PublisherDOI

• Specialized Dendritic Cells Mediating Peripheral Tolerance to Intestinal Antigens

  Immunological Reviews · 2025-12-02 · 1 citations

  articleOpen accessSenior authorCorresponding

  The immune system is tasked with mounting effective responses to pathogens while preventing inflammation triggered by innocuous antigens, including those derived from self, food, and commensal microbes. This balance is especially critical in the intestine, where dietary and microbial antigens are constantly encountered. Peripherally induced regulatory T cells (pTreg or iTreg) play a key role in suppressing inappropriate immune activation and maintaining gut homeostasis. Elucidating how pTreg cells are generated along the gastrointestinal tract is therefore critical to understanding peripheral tolerance. Recent studies have revealed that intestinal antigen-specific pTreg cell differentiation is induced by a distinct lineage of antigen-presenting cells (APCs) requiring expression of the transcription factors RORγt and PRDM16. Genetic perturbation of these APCs results not only in microbiota-specific proinflammatory T cell responses but also in the breakdown of oral tolerance, which in turn predisposes to allergic inflammation. In this review, we summarize the discovery of these tolerance-inducing APCs, highlight their role in instructing pTreg cell differentiation in response to microbiota and dietary antigens, and discuss the regulatory networks that support their function during intestinal immune tolerance.

  PublisherOA PDFDOI

• Author Correction: Unravelling cysteine-deficiency-associated rapid weight loss

  Nature · 2025-12-12

  erratumOpen access
  PublisherOA PDFDOI

Recent grants

• NIH Grant R01AI023513

  NIH · $841k · 1995

• A network model of the gut host-microbe ecosystem in Inflammatory Bowel Disease

  NIH · $632k · 2014–2019

• NIH Grant R01AI033303

  NIH · $1.4M · 1997

• A network model of the gut host-microbe ecosystem in Inflammatory Bowel Disease

  NIH · $2.5M · 2014–2019

• NIH Grant RC2AR058986

  NIH · $4.0M · 2012

Frequent coauthors

• Mary Jean Sunshine

  139 shared

• Vineet N. KewalRamani

  National Cancer Institute

  107 shared

• Steffen Jung

  Weizmann Institute of Science

  100 shared

• Richard Bonneau

  100 shared

• Nigel Killeen

  87 shared

• Wilfried Ellmeier

  Medical University of Vienna

  77 shared

• Nicolas Manel

  Inserm

  55 shared

• Derya Unutmaz

  Jackson Laboratory

  54 shared

Labs

• Health Tech HubPI