About

Professor Franck Barrat holds the Michael R. Bloomberg Chair in Autoimmune Diseases at Hospital for Special Surgery and is a Professor of Microbiology and Immunology at the Weill Cornell Medical College of Cornell University. He graduated from the Pasteur Institute and earned his PhD from the University of Paris. Dr. Barrat completed his postdoctoral fellowship at the DNAX Research Institute in Palo Alto, California. Before joining Hospital for Special Surgery, he spent 15 years working in the biotechnology and pharmaceutical industry in the USA, focusing his research on autoimmune and infectious diseases. His laboratory's main research interest centers on understanding nucleic acid recognition in the context of autoimmunity, particularly exploring the potential clinical benefits of interfering with nucleic acid signaling in human diseases. The lab employs both human and mouse models to study the impact of self nucleic acid recognition on end-organ damage, with a special focus on skin diseases such as scleroderma and systemic lupus erythematosus. Additionally, the lab investigates how the skin micro-environment influences cellular responses in both normal and pathogenic conditions. Many of the lab's projects are conducted in close collaboration with clinicians at the hospital, who provide patient samples and clinical expertise.

Research topics

• Cell biology
• Biology
• Virology
• Immunology
• Genetics

Selected publications

• Escape From X Chromosome Inactivation as a Driver of Plasmacytoid <scp>DC</scp> Heterogeneity in Health and Disease

  Immunological Reviews · 2025-11-01 · 2 citations

  articleOpen access1st authorCorresponding

  Decades of experimental work have helped define the heterogeneity of the various cell types that compose the immune system. The different cell types arise from distinct hematopoietic stem and progenitor cells in a coordinated fashion during ontogeny, providing a set of diverse cells that contribute to host defense. Cells can also differentiate into different subsets in response to the cytokine and tissue environment, creating a level of cellular heterogeneity that helps direct the nature and magnitude of the immune response. Here we are discussing a variation whereby cellular heterogeneity arises due to the expression of X-linked immune genes that escape X chromosome inactivation, giving an advantage to a subset of cells more prone to respond to stimulation by external (pathogens) but also internal signals (i.e., mechanosensing). Interestingly, these inflammatory subsets are much more likely to be differentially enriched in patients with autoimmunity or inflammatory diseases which are well known to be predominant in females. We are using plasmacytoid dendritic cells (pDCs) as a model cell type, as these cells are a rare but critical subset of innate immune cells, with a rapid and massive capacity to produce type I IFNs (IFN-I) upon sensing of nucleic acids from pathogens, but also from the self, and these cells have been linked to the pathogenesis of many autoimmune diseases.

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• The immunoproteasome regulates ILC2 responses by modulating mitochondrial capacity

  Proceedings of the National Academy of Sciences · 2025-11-20 · 2 citations

  articleOpen accessSenior authorCorresponding

  Type 2 innate lymphoid cells (ILC2s) contribute to type 2 immunity but have also been associated with multiple inflammatory diseases, including airway inflammation and asthma. We report that beyond its function of degrading poly-ubiquitinylated proteins, the immunoproteasome (i-20S) is required for the proper function of ILC2s by controlling their mitochondrial capacity. We found that 90% of the catalytic β subunits of proteasomes in human ILC2s (hILC2s) are the immuno- (β5i) rather than constitutive (β5c) isoform. Specific, noncovalent, reversible inhibition of i-20S β5i (LMP7) in hILC2s induced ROS production, which inhibited aconitase, leading to altered mitochondrial function and reduced levels of ATP. Reprogramming of metabolic status by an LMP7 inhibitor impaired ILC2 activation, without significant cytotoxicity or preventing their recovery. Hence, the selective inhibition of i-20S in ILC2 cells did not kill them but reversibly depleted their ATP, preventing their activation and cytokine secretion. In mice, proteasome inhibition similarly blocked mitochondrial function and ILC2 activation, preventing airway inflammation in response to IL33 and asthma in response to house dust mites. These findings reveal a previously unappreciated linkage between proteasome blockade, central carbon metabolism, and mitochondrial function and identify a strategy to regulate immune cell metabolism in inflammatory diseases.

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• RNA N-glycosylation enables immune evasion and homeostatic efferocytosis

  Nature · 2025-08-06 · 35 citations

  articleOpen access
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• Altered X-chromosome inactivation of the TLR7/8 locus and heterogeneity of pDCs in systemic sclerosis

  The Journal of Experimental Medicine · 2024-12-13 · 20 citations

  articleOpen accessSenior author

  Systemic sclerosis (SSc) is an autoimmune disease that has a strong female predominance. Both the X-linked TLR7 and TLR8 can induce type I IFN (IFN-I) by plasmacytoid DCs (pDCs), which can promote fibrosis. We identified five subclusters of pDCs, including ISGhigh clusters that were over-represented in SSc patients. We observed that both TLR7 and TLR8 genes escape from X chromosome inactivation (XCI) at higher frequency in pDCs of SSc patients, which was associated with changes in TLR7 protein profile. Combined DNA/RNA FISH analysis revealed that the TLR7/8 locus is preferentially located outside of the inactive X (Xi) territory when TLR7 is expressed, suggesting that higher-order loop formation is linked to TLR7/8 expression from the Xi. Furthermore, the expression levels of XIST and the transcriptional repressor SPEN were reduced in SSc pDCs. Hence, our data revealed the heterogeneity of pDCs in SSc and suggested that altered XCI at the TLR7/8 locus may contribute to the chronic IFN-I activity of pDCs in female SSc patients.

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• Mechanosensing regulates pDC activation in the skin through NRF2 activation

  The Journal of Experimental Medicine · 2024-12-13 · 10 citations

  articleOpen accessSenior author

  Plasmacytoid DCs (pDCs) infiltrate the skin, chronically produce type I interferon (IFN-I), and promote skin lesions and fibrosis in autoimmune patients. However, what controls their activation in the skin is unknown. Here, we report that increased stiffness inhibits the production of IFN-I by pDCs. Mechanistically, mechanosensing activates stress pathways including NRF2, which induces the pentose phosphate pathway and reduces pyruvate levels, a product necessary for pDC responses. Modulating NRF2 activity in vivo controlled the pDC response, leading to resolution or chronic induction of IFN-I in the skin. In systemic sclerosis (SSc) patients, although NRF2 was induced in skin-infiltrating pDCs, as compared with blood pDCs, the IFN response was maintained. We observed that CXCL4, a profibrotic chemokine elevated in fibrotic skin, was able to overcome stiffness-mediated IFN-I inhibition, allowing chronic IFN-I responses by pDCs in the skin. Hence, these data identify a novel regulatory mechanism exerted by the skin microenvironment and identify points of dysregulation of this mechanism in patients with skin inflammation and fibrosis.

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• Modulation of plasmacytoid dendritic cells response in inflammation and autoimmunity

  Immunological Reviews · 2024-03-29 · 23 citations

  reviewOpen accessSenior authorCorresponding

  The discovery of toll-like receptors (TLRs) and the subsequent recognition that endogenous nucleic acids (NAs) could serve as TLR ligands have led to essential insights into mechanisms of healthy immune responses as well as pathogenic mechanisms relevant to systemic autoimmune and inflammatory diseases. In systemic lupus erythematosus, systemic sclerosis, and rheumatoid arthritis, NA-containing immune complexes serve as TLR ligands, with distinct implications depending on the additional immune stimuli available. Plasmacytoid dendritic cells (pDCs), the robust producers of type I interferon (IFN-I), are providing critical insights relevant to TLR-mediated healthy immune responses and tissue repair, as well as generation of inflammation, autoimmunity and fibrosis, processes central to the pathogenesis of many autoimmune diseases. In this review, we describe recent data characterizing the role of platelets and NA-binding chemokines in modulation of TLR signaling in pDCs, as well as implications for how the IFN-I products of pDCs contribute to the generation of inflammation and wound healing responses by monocyte/macrophages. Chemokine modulators of TLR-mediated B cell tolerance mechanisms and interactions between TLR signaling and metabolic pathways are also considered. The modulators of TLR signaling and their contribution to the pathogenesis of systemic autoimmune diseases suggest new opportunities for identification of novel therapeutic targets.

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• TLR9 ligand sequestration by chemokine CXCL4 negatively affects central B cell tolerance

  The Journal of Experimental Medicine · 2023-09-29 · 16 citations

  articleOpen accessCorresponding

  Central B cell tolerance is believed to be regulated by B cell receptor signaling induced by the recognition of self-antigens in immature B cells. Using humanized mice with defective MyD88, TLR7, or TLR9 expression, we demonstrate that TLR9/MYD88 are required for central B cell tolerance and the removal of developing autoreactive clones. We also show that CXCL4, a chemokine involved in systemic sclerosis (SSc), abrogates TLR9 function in B cells by sequestering TLR9 ligands away from the endosomal compartments where this receptor resides. The in vivo production of CXCL4 thereby impedes both TLR9 responses in B cells and the establishment of central B cell tolerance. We conclude that TLR9 plays an essential early tolerogenic function required for the establishment of central B cell tolerance and that correcting defective TLR9 function in B cells from SSc patients may represent a novel therapeutic strategy to restore B cell tolerance.

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• TLR8 escapes X chromosome inactivation in human monocytes and CD4+ T cells

  Biology of Sex Differences · 2023-09-18 · 47 citations

  articleOpen access

  BACKGROUND: Human endosomal Toll-like receptors TLR7 and TLR8 recognize self and non-self RNA ligands, and are important mediators of innate immunity and autoimmune pathogenesis. TLR7 and TLR8 are, respectively, encoded by adjacent X-linked genes. We previously established that TLR7 evades X chromosome inactivation (XCI) in female immune cells. Whether TLR8 also evades XCI, however, has not yet been explored. METHOD: T lymphocytes from women, Klinefelter syndrome (KS) men, and euploid men. To assign X chromosome territories in cells lacking robust expression of a XIST compartment, we designed probes specific for X-linked genes that do not escape XCI and therefore robustly label the active X chromosome. We also assessed whether XCI escape of TLR8 was associated with sexual dimorphism in TLR8 protein expression by western blot and flow cytometry. RESULTS: Using RNA FISH, we show that TLR8, like TLR7, evades XCI in immune cells, and that cells harboring simultaneously TLR7 and TLR8 transcript foci are more frequent in women and KS men than in euploid men, resulting in a sevenfold difference in frequency. This transcriptional bias was again observable when comparing the single X of XY males with the active X of cells from females or KS males. Interestingly, TLR8 protein expression was significantly higher in female mononuclear blood cells, including all monocyte subsets, than in male cells. CONCLUSIONS: T cells. Co-dependent transcription from the active X chromosome and escape from XCI could both contribute to higher TLR8 protein abundance in female cells, which may have implications for the response to viruses and bacteria, and the risk of developing inflammatory and autoimmune diseases.

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• Data from Tumor-Derived Lysophosphatidic Acid Blunts Protective Type I Interferon Responses in Ovarian Cancer

  2023-04-04

  preprintOpen access

  &lt;div&gt;Abstract&lt;p&gt;Lysophosphatidic acid (LPA) is a bioactive lipid enriched in the tumor microenvironment of immunosuppressive malignancies such as ovarian cancer. Although LPA enhances the tumorigenic attributes of cancer cells, the immunomodulatory activity of this phospholipid messenger remains largely unexplored. Here, we report that LPA operates as a negative regulator of type I interferon (IFN) responses in ovarian cancer. Ablation of the LPA-generating enzyme autotaxin (ATX) in ovarian cancer cells reprogrammed the tumor immune microenvironment, extended host survival, and improved the effects of therapies that elicit protective responses driven by type I IFN. Mechanistically, LPA sensing by dendritic cells triggered PGE&lt;sub&gt;2&lt;/sub&gt; biosynthesis that suppressed type I IFN signaling via autocrine EP4 engagement. Moreover, we identified an LPA-controlled, immune-derived gene signature associated with poor responses to combined PARP inhibition and PD-1 blockade in patients with ovarian cancer. Controlling LPA production or sensing in tumors may therefore be useful to improve cancer immunotherapies that rely on robust induction of type I IFN.&lt;/p&gt;Significance:&lt;p&gt;This study uncovers that ATX–LPA is a central immunosuppressive pathway in the ovarian tumor microenvironment. Ablating this axis sensitizes ovarian cancer hosts to various immunotherapies by unleashing protective type I IFN responses. Understanding the immunoregulatory programs induced by LPA could lead to new biomarkers predicting resistance to immunotherapy in patients with cancer.&lt;/p&gt;&lt;p&gt;&lt;i&gt;&lt;a href="https://aacrjournals.org/cancerdiscovery/article/doi/10.1158/2159-8290.CD-22-0611" target="_blank"&gt;See related commentary by Conejo-Garcia and Curiel, p. 1841&lt;/a&gt;.&lt;/i&gt;&lt;/p&gt;&lt;p&gt;&lt;i&gt;&lt;a href="https://aacrjournals.org/cancerdiscovery/article/doi/10.1158/2159-8290.CD-12-8-ITI" target="_blank"&gt;This article is highlighted in the In This Issue feature, p. 1825&lt;/a&gt;&lt;/i&gt;&lt;/p&gt;&lt;/div&gt;

  PublisherDOI

• Supplementary Figure from Tumor-Derived Lysophosphatidic Acid Blunts Protective Type I Interferon Responses in Ovarian Cancer

  2023-04-04

  preprintOpen access

  Supplementary Figure from Tumor-Derived Lysophosphatidic Acid Blunts Protective Type I Interferon Responses in Ovarian Cancer

  PublisherOA PDFDOI

Recent grants

• Role of plasmacytoid dendritic cells in autoimmunity

  NIH · $2.2M · 2018–2024

Frequent coauthors

• Lionel B. Ivashkiv

  Hospital for Special Surgery

  59 shared

• Geneviève de Saint Basile

  51 shared

• Alain Fischer

  Hôpital Necker-Enfants Malades

  48 shared

• Marie Dominique Ah Kioon

  Hospital for Special Surgery

  44 shared

• Françoise Le Deist

  Centre Hospitalier Universitaire Sainte-Justine

  42 shared

• Yong Du

  Cornell University

  37 shared

• Vidyanath Chaudhary

  Hospital for Special Surgery

  37 shared

• Jérôme Feldmann

  Centre National de la Recherche Scientifique

  34 shared