IFN-: The T cell’s license to kill stem cells in the inflamed intestine – Science
By daniellenierenberg
Abstract
IFN- produced by T cells directly induces intestinal stem cell death upon inflammation-induced intestinal injury (see the related Research Article by Takashima et al.).
Intestinal regeneration upon tissue damage is fueled by intestinal stem cells (ISCs) residing in the crypt bottom of the epithelium and marked by the gene Lgr5 (1, 2). There is growing evidence that tissue repair is at least partially mediated by a regenerative inflammatory response (3, 4). How inflammation-induced intestinal injury influences ISCs and their microenvironment (stem cell niche) remains poorly understood. In this issue of Science Immunology, Takashima et al. (5) explore the changes in the ISC niche in vivo upon T cellmediated injury as a model of graft-versus-host disease (GVHD) and in vitro using organoid T cell cocultures. Although earlier studies already implicated interferon- (IFN-) as a negative regulator of intestinal epithelial homeostasis (68), Takashima et al. now demonstrate that IFN- directly acts on ISCs by triggering apoptosis.
In an allogeneic bone marrow transplant (BMT) model, Takashima and colleagues found that ISC numbers per intestinal crypt were markedly reduced in mice receiving bone marrow alone or bone marrow and T cells when compared with normal control mice. While the ISCs in the mice receiving only bone marrow recovered 7 days later, the ISC numbers remained reduced in those mice also transplanted with donor T cells. Of note, Paneth cell numbers were also reduced after ISC depletion. The numbers of organoids established from the intestines of mice 10 days after BMT recovered back to that of control mice, whereas the organoid forming capacity from crypts of mice after combined transplantation of bone marrow and T cells remained significantly lower. Similar in vivo and in vitro results were obtained when autoreactive T cells were transplanted, pointing to a common feature of T cellmediated intestinal injury.
As seen by three-dimensional confocal microscopy, intraepithelial T cells (CD3+ IELs) preferentially localized to the villus region, whereas lamina propriaassociated T cells (CD3+ LPLs) were equally distributed along the crypt-villus axis of control mice (Fig. 1A). Conversely, mice receiving bone marrow and allogeneic T cells showed a progressive increase in the density of both CD3+ LPLs and CD3+ IELs in the crypt region.
To identify signaling molecules that cause the loss of ISCs in this model, Takashima and colleagues performed several elegant murine and human epithelial organoid coculture experiments. Murine nave allogeneic T cells did not impair murine intestinal organoid numbers, whereas alloreactive T cells effectively reduced organoid numbers. Likewise, human allogeneic cytotoxic T cells robustly inhibited human intestinal organoid forming efficiency. Even bead-activated autologous T cells suppressed human intestinal organoid growth. The authors then proceeded to screen for potential pathways mediating cytotoxicity. Organoids cocultured with T cells in the presence of antiIFN- neutralizing antibodies showed normal growth. Although IFN- receptor (IFN-R)depleted T cells were still able to affect organoid viability, IFN-Rdepleted organoids were resistant to T cellmediated killing. Organoid toxicity by IFN- was also observed in the absence of T cells. Live imaging confirmed the progressive ISC depletion upon organoid exposure to IFN-. Treatment of organoids with the immunosuppressive JAK1/2 inhibitor ruxolitinib robustly preserved numbers of both organoids and ISCs in the presence of IFN-, irrespective of whether the organoids were cultured alone or together with T cells. The authors additionally demonstrated that JAK1-depleted organoids are resistant to IFN- treatment. Further downstream, ruxolitinib prevented STAT1 phosphorylation by IFN- in intestinal crypts, and, in line, STAT1-depleted organoids were resistant to growth suppression in response to IFN- treatment.
IFN-treated organoids showed reduced expression of ISC marker genes. ISCs underwent apoptosis in vitro in a direct response to IFN-. Next, the authors confirmed in vivo that ISC numbers did not change upon transplanting allogeneic bone marrow and T cells when treating mice with IFN- neutralizing antibodies. Likewise, ruxolitinib treatment protected ISCs from T cellmediated killing in vivo. Donor T cells, particularly T helper 1 cells, were activated and IFN-+. Transplanting IFN-depleted allogeneic T cells robustly reduced the ISC loss and allowed epithelial cell proliferation to increase.
Takashima and colleagues lastly investigated whether IFN- directly induces ISC apoptosis. Using tissue-specific depletion of IFN-R1, the authors found that epithelial loss of the receptor protects from the immune-mediated GVHD phenotype. IFN-R1 is expressed by both ISCs and Paneth cells, the epithelial component of the ISC niche (9). However, Paneth celldeficient organoids remained sensitive to both IFN- and allogeneic T cellmediated cytotoxicity. Likewise, T cells were able to reduce the number of organoids containing IFN-R1deficient Paneth cells, whereas organoids containing IFN-R1deficient ISC were protected from cytotoxicity. The authors demonstrated in further experiments that IFN- directly induces ISC apoptosis independent of Paneth cells (Fig. 1, B and C).
The study by Takashima et al. extends our knowledge on signaling between ISCs and immune cells, identifying ISCs as direct targets of IFN- secreted by T cells in immune-mediated intestinal damage (as caused by GVHD). In the 2015 study by Lindemans et al., this group already identified that interleukin-22 (IL-22) secreted by group 3 innate lymphoid cells (ILC3s) directly stimulates ISCs to proliferate and regenerate the intestinal epithelium upon inflammation-induced intestinal injury (4). Modulating the effects of T cellderived IFN- on ISC, for instance, by suppressing JAK/STAT signaling via ruxolitinib treatment, may provide a new therapeutic avenue to reducing GVHD-induced damage of the intestinal epithelium (10).
(A) ISCs maintain adult homeostasis of the intestinal epithelium. T lymphocytes patrol the intestine. (B) Takashima et al. show that in GVHD as modeled by BMT and aberrant activation of T lymphocytes, T cellderived IFN- directly acts on ISCs and induces apoptosis via JAK/STAT signaling. (C) Disease progression results in marked intestinal damage due to loss of ISCs and their niche.
Acknowledgments: Funding: K.K. is a long-term fellow of the Human Frontier Science Program Organization (LT771/2015). Competing interests: H.C. and K.K. are named inventors on patents or patents pending on Lgr5 stem cellbased organoid technology.
Follow this link:
IFN-: The T cell's license to kill stem cells in the inflamed intestine - Science
- Rejuvenating the immune system by depleting certain stem cells - National Institutes of Health (NIH) (.gov) - April 19th, 2024
- New gene therapy eliminates need for bone marrow transplant. Here's how it works. - CBS News - April 19th, 2024
- New gene therapy eliminates need for bone marrow transplant. Here's how it works. - MSN - April 19th, 2024
- Long Island boy with rare blood disorder undergoes gene therapy - MSN - April 19th, 2024
- Philadelphia Wings player, Connecticut man will be forever bonded by bone marrow donation: "He's my hero" - CBS Philly - April 10th, 2024
- VRD versus VCD as induction therapy before autologous stem cell transplantation in multiple myeloma: a nationwide ... - Nature.com - April 10th, 2024
- Register as a bone marrow donor today and save lives - The Citizen - April 10th, 2024
- Resilient anatomy and local plasticity of naive and stress haematopoiesis - Nature.com - March 26th, 2024
- A Deeper Depth of Response After Salvage Therapy Improves Outcomes of Autologous Stem Cell Transplantation in ... - Cureus - March 26th, 2024
- Iron restriction keeps blood stem cells young, researchers find - Phys.org - March 18th, 2024
- Blood drive, bone marrow testing to be held in local woman's memory - The Winchester Star - March 18th, 2024
- Signal of Benefit for Stem Cell Therapy in Progressive MS - Medscape - March 10th, 2024
- Woman, 22, With Leukemia Recalls Symptoms And New Treatment She Received: EXCLUSIVE - TODAY - March 10th, 2024
- This Swedish startup wants to reduce the cost, and controversy, around stem cell production - TechCrunch - March 10th, 2024
- Outcomes and prognosis of haploidentical haematopoietic stem cell transplantation in children with FLT3-ITD mutated ... - Nature.com - March 10th, 2024
- Harmonizing definitions for hematopoietic recovery, graft rejection, graft failure, poor graft function, and donor ... - Nature.com - March 10th, 2024
- Hematopoietic cell transplantation and cell therapy activity landscape survey in the Kingdom of Saudi Arabia; a report ... - Nature.com - March 10th, 2024
- How an MS friendship led to HSCT and a love of running - Multiple Sclerosis News Today - March 10th, 2024
- Iron Limitation Preserves Youthfulness of Blood Stem Cells - Mirage News - March 10th, 2024
- Allogeneic Hematopoietic Cell Transplantation in Advanced Systemic Mastocytosis: A retrospective analysis of the ... - Nature.com - March 10th, 2024
- AJMC in the Press, February 23, 2024 - AJMC.com Managed Markets Network - February 24th, 2024
- Orca Bio Presents Promising Data on Orca-T in Two Oral Presentations at the 2024 Tandem Meetings of ASTCT and ... - Yahoo Finance - February 24th, 2024
- New approaches to live-track the production of different types of blood cells in mice - Medical Xpress - February 24th, 2024
- If Other Treatments Aren't Working -- Stem Cell Transplant May Be A Good Option In CLL - SurvivorNet - February 24th, 2024
- Expanding the Horizons of Cell and Gene Therapy - RegMedNet - February 24th, 2024
- The strangers who saved each others lives - BBC - February 24th, 2024
- City of Hope Research Featuring the Successful Treatment of the Oldest Patient to Achieve Remission for Leukemia ... - StreetInsider.com - February 15th, 2024
- 3D printing and material processing combined to create artificial bone - Optics.org - February 15th, 2024
- Man, 63, is in remission from HIV five years after receiving groundbreaking stem cell transplant... - The Sun - February 15th, 2024
- Team demonstrates fabrication method to construct 3D structures that mimic bone microstructure - Phys.org - February 15th, 2024
- Hematopoietic Stem Cells and Their Role in Development and Disease Therapy - The Scientist - February 15th, 2024
- Blood cell family trees trace how production changes with aging - MIT News - February 7th, 2024
- New study on promising stem cell-based therapy for Crohn's disease - Medical Xpress - January 30th, 2024
- Second haploidentical bone marrow transplantation with antithymocyte antibody-containing conditioning regimen for ... - Nature.com - January 30th, 2024
- Stem cell study shows how gene activity modulates the amount of immune cell production in mice - Medical Xpress - January 30th, 2024
- Global Stem Cell Therapy Industry Outlook to 2028, Driven by Therapeutic Innovations and Clinical Advancements ... - Yahoo Finance - January 30th, 2024
- 1st-of-its-kind therapy blocks immune attack after stem-cell transplant - Livescience.com - January 22nd, 2024
- Individualized dose of anti-thymocyte globulin based on weight and pre-transplantation lymphocyte counts in pediatric ... - Nature.com - January 22nd, 2024
- Implications of stress-induced gene expression for hematopoietic stem cell aging studies - Nature.com - January 22nd, 2024
- LVHN announces opening of new stem cell transplant center. Here's what that means for the Lehigh Valley - The Morning Call - January 22nd, 2024
- Fast Five Quiz: Chronic GVHD Risk Factors and Prevention - Medscape Reference - January 22nd, 2024
- Could Treatments for HIV and Sickle Cell Open the Gene Therapy Floodgates? - BioSpace - January 22nd, 2024
- Effects of fine particulate matter on bone marrow-conserved hematopoietic and mesenchymal stem cells: a systematic ... - Nature.com - January 14th, 2024
- Donating Bone Marrow and Stem Cells: The Process and What To Expect - On Cancer - Memorial Sloan Kettering - January 14th, 2024
- No, Rep. Steve Scalise Didn't Vote Against Stem Cell Research From Which He Is Now Benefiting - Yahoo News - January 14th, 2024
- Hematopoietic Stem Cell Transplantation Market to Grow Rapidly During the Study Period (2019-2032), Evaluates ... - PR Newswire - January 14th, 2024
- Life-saving donation from Philly athlete saves life: 'Feeling so strong, I owe that all to him' - AOL - January 14th, 2024
- The Key to Creating Blood Stem Cells May Lie in Your Own Blood - ScienceAlert - January 14th, 2024
- Dr Phillips on the Rationale for the GLOBRYTE Trial in Relapsed/Refractory MCL - OncLive - January 14th, 2024
- COVID-19 and HSCT Recipients: Risk Factors and Prevention Measures - Medriva - January 14th, 2024
- Bone Marrow Transplant: Heres What You Need To Know About This Therapy - Times Now - January 5th, 2024
- New insights about the development of hematopoietic stem cells - Drug Target Review - December 28th, 2023
- Bone Marrow Transplantation | Johns Hopkins Medicine - December 20th, 2023
- Stem Cell or Bone Marrow Transplant | American Cancer Society - December 20th, 2023
- Embryonic-stem-cell-derived mesenchymal stem cells relieve experimental contact urticaria by regulating the functions ... - Nature.com - December 20th, 2023
- Researchers discover crucial step in creating blood stem cells - Phys.org - December 20th, 2023
- A niche topic: understanding the development of hematopoietic stem cells - Fred Hutchinson Cancer Center - December 20th, 2023
- Vertex developed a CRISPR cure. Its already on the hunt for something better. - MIT Technology Review - December 20th, 2023
- FDA approves cure for sickle cell disease, the first treatment to use gene-editing tool CRISPR - NBC News - December 12th, 2023
- First therapy using CRISPR technology will treat sickle cell disease - Morning Brew - December 12th, 2023
- 7 medical breakthroughs that gave us hope in 2023 - National Geographic - December 12th, 2023
- Understanding Chronic Myeloid Leukemia: Causes, Symptoms, and Treatment - Everyday Health - December 12th, 2023
- Mansour bin Zayed witnesses inauguration of ADSCC Bone Marrow Transplant & Cellular Therapy Congress 2023 - ZAWYA - November 26th, 2023
- ADSCC Bone Marrow Transplant and Cellular Therapy Congress 2023 to take place in Abu Dhabi - ZAWYA - November 18th, 2023
- Orchard Therapeutics Reports First Quarter 2023 Financial Results and Announces Initiation of Rolling Submission for Biologics License Application of... - May 16th, 2023
- Family of 7-month-old in need of bone marrow transplant hosting donor registration event - CBS Pittsburgh - May 8th, 2023
- Anika Continues to Expand Addressable Market for Tactoset Injectable Bone Substitute with Additional 510(k) Clearance from FDA - Marketscreener.com - April 5th, 2023
- MorphoSys Completes Enrollment of Phase 3 MANIFEST-2 Study of Pelabresib in Myelofibrosis with Topline Results Expected by End of 2023 -... - April 5th, 2023
- VOR BIOPHARMA INC. Management's Discussion and Analysis of Financial Condition and Results of Operations (form 10-K) - Marketscreener.com - March 25th, 2023
- BioRestorative Therapies to Seek FDA Approval to Expand the Clinical Application of BRTX-100 - Marketscreener.com - March 17th, 2023
- BioSenic delivers a new post-hoc analysis of its Phase III JTA-004 trial on knee osteo-arthritis with positive action on the most severely affected... - March 17th, 2023
- JASPER THERAPEUTICS, INC. MANAGEMENT'S DISCUSSION AND ANALYSIS OF FINANCIAL CONDITION AND RESULTS OF OPERATIONS (form 10-K) - Marketscreener.com - March 9th, 2023
- For a range of unmet medical needs, India offers a fantastic opportunity to push cell and gene therapies: B .. - ETHealthWorld - March 9th, 2023
- NGM BIOPHARMACEUTICALS INC Management's Discussion and Analysis of Financial Condition and Results of Operations. (form 10-K) - Marketscreener.com - March 1st, 2023
- Bone health: Tips to keep your bones healthy - Mayo Clinic - January 27th, 2023
- Bone marrow drive held for military wife with cancer - January 27th, 2023
- Bone cancer - Symptoms and causes - Mayo Clinic - January 27th, 2023
- Bone | Definition, Anatomy, & Composition | Britannica - January 19th, 2023
- Bone Definition & Meaning - Merriam-Webster - January 19th, 2023
- What Is Bone? | NIH Osteoporosis and Related Bone Diseases National ... - January 19th, 2023