Immune cells called group 3 innate lymphoid cells (ILC3s) play an essential role in establishing tolerance to symbiotic microbes that dwell in the human gastrointestinal tract, according to a study led by researchers at Weill Cornell Medicine.
The discovery, reported Sept. 7 in Nature, illuminates an important aspect of gut health and mucosal immunityone that may hold the key to better treatments for inflammatory bowel disease (IBD), colon cancer and other chronic disorders.
As part of this study, we define a novel pathway that drives immune tolerance to microbiota in the gastrointestinal tract, said senior author Dr. Gregory F. Sonnenberg, associate professor of microbiology and immunology in medicine and head of basic research in the Division of Gastroenterology & Hepatology, and a member of the Jill Roberts Institute for Research in Inflammatory Bowel Disease at Weill Cornell Medicine. This is a fundamental advance in our understanding of mucosal immunity and may hold the key to understanding what goes wrong when the immune system begins to inappropriately attack microbiota in diseases such as IBD.
Drs.Mengze Lyu and Gregory Sonnenberg
Scientists have long known that trillions of bacteria, fungi, and other microbes dwell symbiotically in the intestines of mammals. The mechanism by which the immune system normally tolerates these beneficial gut microbes, instead of attacking them, has not been well understood. But there is evidence that this tolerance breaks down in IBD, leading to harmful flareups of gut inflammation. Thus, a detailed understanding of gut immune tolerance could enable the development of powerful new treatments for IBDa class of diseases that include Crohns disease and ulcerative colitis, which affect several million individuals in the United States alone.
In the study, Dr. Sonnenberg and colleagues, including lead author Dr. Mengze Lyu, a postdoctoral researcher in the Sonnenberg lab, used single-cell sequencing and fluorescent imaging techniques to delineate immune cells in the mesenteric lymph nodes that drain the intestines of healthy mice. They focused on cells expressing a transcription factor, RORt, which are known to drive either inflammation or tolerance in response to microbes that colonize the intestine. The dominant immune cell types in these tissues, they found, were T cells and ILC3s. The latter are a family of immune cells that represent an innate counterpart of T cells, and work as a first line of defense in mucosal tissues such as the intestines and lungs.
In close collaboration with researchers at the University of Birmingham, UK, the scientists observed that in lymph node regions called interfollicular zones, ILC3s are in close association with a specific type of T cell, called RORt+ regulatory T cells (Tregs), which are adapted to dial down inflammation and immune activity to promote tolerance in the gut.
We previously defined key roles for ILC3s in regulating adaptive immunity, but these findings are exciting as they provoke a concept that ILC3s directly interact with Tregs to control immune tolerance in the gut, said Dr. David R. Withers, professor of immune regulation at the Institute of Immunology and Immunotherapy and the University of Birmingham. Dr. Withers and his laboratory are key contributors to this study and long-term collaborators of Dr. Sonnenberg.
The researchers next found evidence that ILC3s play an essential role in promoting the RORt+Treg population in the gut. Much like how immune responses are generated to disease-causing microbes, the ILC3s present pieces of gut-dwelling microbes; but this elicited RORt+ Tregs that specifically recognize these microbes rather than an inflammatory immune response. These RORt+ Tregs then suppress other T cell responses and enforce tolerance to the microbiota.
The scientists found that when they deleted the surface molecule, MHC class II, that ILC3s use to present microbial antigens, thus impeding ILC3s interactions with RORt+ Tregs, the observed RORt+ Tregs were substantially lower than in normal mice, and the affected mice developed spontaneous gut inflammation. At the same time, inflammatory RORt+ T cells, called T helper (Th)17 cells, were dramatically increased in these micein part because many Tregs, bereft of the usual signals from their ILC3 helpers, turned into Th17 cells.
Our extensive research reveals that ILC3s are necessary and sufficient enforcers of immune tolerance to gut microbes, Dr. Lyu said. In addition, we now have a sophisticated understanding of the signals that ILC3s use to communicate with T cells and drive the generation of microbiota-specific Tregs.
To confirm the potential relevance to humans, the researchers analyzed samples of inflamed gut tissue from pediatric IBD patients or healthy individuals in close collaboration with Dr. Robbyn E. Sockolow, professor of clinical pediatrics and chief of the division of Pediatric Gastroenterology, Hepatology and Nutrition in the Department of Pediatrics at Weill Cornell Medicine and a pediatric gastroenterologist at NewYork-Presbyterian Komansky Children's Hospital and Center for Advanced Digestive Care. With Dr. Socklolow and the Roberts Institute Live Cell Bank, they found evidence that communication between ILC3s and RORt+Tregs is disrupted in IBD patients.
Our exciting results provide a potential explanation for why immune tolerance is impaired in IBD patients, which could provoke new therapies with the goal of re-educating the immune system to limit chronic inflammation directed against the microbiota, Dr. Sockolow said.
Dr. Sonnenberg and colleagues now are trying to determine how the ILC3-T cell tolerance mechanism distinguishes between symbiotic, helpful microbes and disease-causing ones. But the results so far suggest, that future cell therapies to restore ILC3 functionality might have powerful effects in suppressing inflammation in IBD. Further, it remains possible that this pathway could be harnessed to limit other inflammatory and autoimmune disorders, as recently demonstrated by the Sonnenberg Lab in mouse models of multiple sclerosis.
The fact that the ILC3s are essential to orchestrate tolerance by promoting antigen-specific Tregs is particularly important, Dr. Sonnenberg notes, for it suggests the possibility of highly targeted treatments that can precisely suppress a source of inappropriate immune activity without compromising immunity as a whole.
Research in the Sonnenberg Laboratory is supported by the National Institutes of Health (R01AI143842, R01AI123368, R01AI145989, U01AI095608, R21CA249274, R01AI162936 and R01CA274534); an Investigators in the Pathogenesis of Infectious Disease Award from the Burroughs Wellcome Fund; the Meyer Cancer Center Collaborative Research Initiative; The Dalton Family Foundation; the Crohns and Colitis Foundation; and Linda and Glenn Greenberg. Dr. Sonnenberg is a CRI Lloyd J. Old STAR. The JRI IBD Live Cell Bank is supported by the JRI, Jill Roberts Center for IBD, Cure for IBD, the Rosanne H. Silbermann Foundation, the Sanders Family and Weill Cornell Medicine Division of Pediatric Gastroenterology, Hepatology, and Nutrition.
- Cell-Based Regenerative Medicine Market Size to Witness Rapid Growth at a CAGR of 15% by 2032 | insightSLICE - EIN News - May 9th, 2023
- Indian Pharma Congress: Gene-cell therapy, preventive medicine future of health care, says expert - Economic Times - January 21st, 2023
- Cell culture - Wikipedia - December 18th, 2022
- The Legacy of Henrietta Lacks - Hopkins Medicine - December 10th, 2022
- HOME | Stem cell & Cancer - October 4th, 2022
- CAR T Cell Therapy Offers a New Hope in the Treatment of Severe and Refractory Systemic Lupus Erythematosus - Rheumatology Network - October 4th, 2022
- Cell and Gene Therapy: Rewriting the Future of Medicine - Technology Networks - October 4th, 2022
- Outlook on the Automated Cell Counters Global Market to 2028 - Use of Cell Counters in Personalized Medicine Presents Opportunities -... - October 4th, 2022
- Jcr Pharmaceuticals Co., Ltd. and Sysmex Establish A Joint Venture in the Field of Regenerative Medicine and Cell Therapy - Marketscreener.com - October 4th, 2022
- Growth in Cell and Gene Therapy Market - BioPharm International - October 4th, 2022
- Breakthrough in production of cancer-treating drug - Stanford University News - October 4th, 2022
- CRISPR Therapeutics Announces FDA Regenerative Medicine Advanced Therapy (RMAT) Designation Granted to CTX130 for the Treatment of Cutaneous T-Cell... - October 4th, 2022
- Mary Munson elected fellow of the American Society for Cell Biology - UMass Medical School - October 4th, 2022
- 5 FDA decisions to watch in the fourth quarter - BioPharma Dive - October 4th, 2022
- bit.bio Adds Two New Human Cell Products to Address the Translation Gap and Accelerate Research and Drug Discovery for Neurodegenerative Disease -... - October 4th, 2022
- Laser Focus World highlights UC research that uses light to restore cell function - University of Cincinnati - October 4th, 2022
- The Institute of Regenerative Medicine | Non-Surgical, Cell-Based ... - September 25th, 2022
- CAR T-Cell Therapy Shows Promise in Treating Lupus - Healthline - September 25th, 2022
- ProKidney to Present at the Jefferies Cell and Genetic Medicine Summit - El Paso Inc. - September 25th, 2022
- Allogene Therapeutics Announces Participation in the Jefferies Cell and Genetic Medicine Summit - GlobeNewswire - September 25th, 2022
- Alzheimer's disease risk linked to newly discovered protein mutation - Medical News Today - September 25th, 2022
- Biological Links Identified Between an Aggressive Breast Cancer Type and African Ancestry - Weill Cornell Medicine Newsroom - September 25th, 2022
- The Use of Nanorobotics in the Treatment Therapy of Cancer and Its Future Aspects: A Review - Cureus - September 25th, 2022
- UW Health, UW-Madison School of Medicine and Public Health: Innovative clinical trial targets recurrent BK infection in kidney transplant recipients -... - September 25th, 2022
- Shutting down backup genes leads to cancer remission in mice - University of Michigan News - September 25th, 2022
- Pembrolizumab in Combination with Lenvatinib as First-Line Treatment for Non Clear Cell Renal Cell Carcinoma (nccRCC), KEYNOTE-B61 - Laurence Albiges... - September 25th, 2022
- FDA's ODAC Votes That Benefits Do Not Outweigh Risks for Poziotinib in HER Exon 20 Ins+ NSCLC - Targeted Oncology - September 25th, 2022
- Courageous Lanarkshire teen who survived leukaemia thanks to a clinical trial pursues nursing dream - Daily Record - September 25th, 2022
- Study: New Factors Are Associated With Increased PFS from BCMA-Targeted T-Cell Therapy - Pharmacy Times - September 8th, 2022
- Study Uncovers Possible Path for Improving T Cell Therapies - University of Arizona - September 8th, 2022
- Trodelvy Significantly Improved Overall Survival in Pre-Treated HR+/HER2- Metastatic Breast Cancer Patients in TROPiCS-02 Study - Gilead Sciences - September 8th, 2022
- Manipulating Astrocytes in Tumor Environment Effective Against Glioblastoma - Inside Precision Medicine - September 8th, 2022
- Jane Fonda Diagnosed with Non-Hodgkin's Lymphoma: What to Know - Healthline - September 8th, 2022
- Dr Hatim Husain: Biomarker Testing Is a Treatment Cornerstone in NSCLC - AJMC.com Managed Markets Network - August 30th, 2022
- Porton Advanced and Kun Tuo Announce Strategic Partnership to Deepen Gene and Cell Therapy CDMO and Clinical Research Services - PR Newswire - August 30th, 2022
- The Role of Eosinophils as a Biomarker to Inform Treatment Decisions for Patients With COPD - Consultant360 - August 30th, 2022
- Scientists Discover Surprise Anticancer Properties of Common Lab Molecule | Newsroom - UNC Health and UNC School of Medicine - August 30th, 2022
- Overall survival is similar for patients receiving CT-based or minimal follow-up after surgical resection of non-small-cell lung cancer - 2 Minute... - August 30th, 2022
- NSF Grant to Aid OSU Researchers Developing Treatment for Canine Cancer - The Corvallis Advocate - August 30th, 2022
- Researchers Identify the Target of Immune Attacks on Liver Cells in Metabolic Disorders - Weill Cornell Medicine Newsroom - August 22nd, 2022
- Why Is CAR T-Cell Therapy One of the Most Phenomenal Advances in Science? - University of Colorado Anschutz Medical Campus - August 22nd, 2022
- Porton Advanced Solutions completes a Series B financing round to expand its end-to-end Gene and Cell Therapy CDMO Platforms - PR Newswire - August 22nd, 2022
- Cell Analysis Global Market Report 2022: Growing Focus on Personalized Medicine & Introduction of Advanced Technologies in Cell Analysis Presents... - August 22nd, 2022
- Stress can throw off circadian rhythms and lead to weight gain - Medical News Today - August 22nd, 2022
- Cell Stress and Mitochondrial Dysfunction Found in Early Alzheimers Disease Patients, Findings Published in Science Translational Medicine - BioSpace - August 22nd, 2022
- Restoring cell and organ function after the heart stops - National Institutes of Health (.gov) - August 22nd, 2022
- Rolling the Dice: Gamble Pays Off For Cancer Patient in CAR T-Cell Clinical Trial - University of Colorado Anschutz Medical Campus - August 22nd, 2022
- Boosting neuron formation restores memory in mice with Alzheimer's disease - EurekAlert - August 22nd, 2022
- UTSW study finds p53 gene plays second role in suppressing genes tied to cancer - UT Southwestern - August 22nd, 2022
- GlyNAC supplementation reverses mitochondrial dysfunction, oxidative stress and aging hallmarks to boost strength and promote health in aging humans -... - August 22nd, 2022
- Multiple shots of the BCG vaccine protect type 1 diabetics from COVID-19 - EurekAlert - August 22nd, 2022
- Cell Regeneration Medicine Market Analysis by Type, Application, Growth, Demand, Status, and Forecast from 2022 to 2032 - Digital Journal - August 5th, 2022
- Higher Hydroxyurea Exposure Tied to Better Blood Parameters in US... - Sickle Cell Anemia News - August 5th, 2022
- Kiwis with multiple sclerosis patients thriving from overseas stem-cell treatment urge Government to approve it here - Newshub - July 27th, 2022
- MHRA grants marketing authorisation to Global Blood Therapeutics for sickle cell disease drug - PMLiVE - July 27th, 2022
- CAR T-Cell Therapy Turns 10 and Finally Earns the Word 'Cure' - Medscape - July 27th, 2022
- Oncology Peer Review On-The-Go: The Prognostic Significance of Peripheral Blood Biomarkers in Patients With Advanced NonSmall Cell Lung Cancer Treated... - July 27th, 2022
- CRISPR therapeutics can damage the genome - EurekAlert - July 27th, 2022
- To cell surface and beyond: Tracing subcellular glycoprotein transport using modified cholera toxin - EurekAlert - July 27th, 2022
- From Donor to Patient: Advancing the Future of Cell Therapies - Genetic Engineering & Biotechnology News - July 27th, 2022
- Five-Year Review of Biomedical Research Imaging Center, Center Director | Newsroom - UNC Health and UNC School of Medicine - July 27th, 2022
- Using Particles That Are Smaller Than the Head of a Pin to Treat Cancer - Yale School of Medicine - July 11th, 2022
- Stem Cell Assays Market Report 2022-2027: Increasing Awareness About Therapeutic Potency of Stem Cells Driving Growth - ResearchAndMarkets.com -... - July 11th, 2022
- Sickle cell disease could be treated with common plant, study finds - The Telegraph - July 11th, 2022
- Unexpected link between most common cancer drivers may yield more effective drugs - University of Wisconsin-Madison - July 11th, 2022
- Scientists Discover Key to Hepatitis A Virus Replication, Show Drug Effectiveness | Newsroom - UNC Health and UNC School of Medicine - July 11th, 2022
- How Erectile Dysfunction Drugs Can Help Treat Cancer and Save Thousands of Lives - SciTechDaily - July 11th, 2022
- Pune: Dr Mohan Wani appointed as director of National Centre for Cell Science - The Indian Express - July 11th, 2022
- Kite's CAR T-cell Therapy Yescarta Granted European Marketing Authorization for the Treatment of Relapsed or Refractory Follicular Lymphoma - Gilead... - July 3rd, 2022
- Important Factors for Regulating the Body's Immune Response - Neuroscience News - July 3rd, 2022
- Stem Cell Therapy Market Is Expected To Reach USD 455.61 Billion By 2027 At A CAGR Of 16 percent By Forecast 2027 Says Maximize Market Research (MMR)... - July 3rd, 2022
- Neurona Therapeutics Announces Initial Subject Dosed in First Clinical Trial of Regenerative Human Cell Therapy, NRTX-1001, in Adults with... - July 3rd, 2022
- Growing scope of Genetic Medicine and Stem Cell Research - The Hindu - June 22nd, 2022
- When children with sickle cell grow up, they face a system not designed for them - 89.3 WFPL News Louisville - June 22nd, 2022
- Precision BioSciences Announces In Vivo Gene Editing Collaboration with Novartis to Develop Potentially Curative Treatment for Disorders Including... - June 22nd, 2022
- Stem Cell Assays Market worth $4.5 billion by 2027 - Exclusive Report by MarketsandMarkets - PR Newswire - June 22nd, 2022
- Bringing heart and humanity to hematology | News | Harvard TH Chan School of Public Health - HSPH News - June 22nd, 2022
- Belzutifan Improves Survival in Patients With RCC and VHL - Targeted Oncology - June 22nd, 2022
- Immatics and Editas Medicine Enter Strategic Research Collaboration and Licensing Agreement to Combine Gamma-Delta T Cell Adoptive Cell Therapies and... - June 13th, 2022
- ASCO 2022: Gilead's tough weekend, bispecific progress and 'gamma delta' cell therapy - BioPharma Dive - June 13th, 2022