Hector Rodriguez Cetina Biefer1, Timm Heinbokel2, Hirofumi Uehara3, Virginia Camacho4, Koichiro Minami5, Yeqi Nian5, Suresh Koduru6, Rachid El Fatimy7, Ionita Ghiran8, Alexander J Trachtenberg9, Miguel A de la Fuente10, Haruhito Azuma3, Omid Akbari11, Stefan G Tullius5, Anju Vasudevan12, Abdallah Elkhal13. 1. Division of Transplant Surgery and Transplantation Surgery Research Laboratory, Brigham and Women's Hospital, Harvard Medical School, Boston, Mass; Clinic for Cardiovascular Surgery, University Hospital Zurich, Zurich, Switzerland. 2. Division of Transplant Surgery and Transplantation Surgery Research Laboratory, Brigham and Women's Hospital, Harvard Medical School, Boston, Mass; Department of Nephrology, Charite Universitaetsmedizin Berlin, Berlin, Germany. 3. Department of Urology, Osaka Medical College, Osaka, Japan. 4. Flow Cytometry Core Facility, Beth Israel Deaconess Medical Center, Harvard Stem Cell Institute, Boston, Mass. 5. Division of Transplant Surgery and Transplantation Surgery Research Laboratory, Brigham and Women's Hospital, Harvard Medical School, Boston, Mass. 6. School of Medical Sciences, University of Hyderabad, Hyderabad, India. 7. Department of Neurology, Center for Neurologic Diseases, Initiative for RNA Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Mass. 8. Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Stem Cell Institute, Boston, Mass. 9. StART Families, Boston, Mass. 10. Instituto de Biología y Genética Molecular, University of Valladolid, Valladolid, Spain. 11. Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, Calif. 12. Angiogenesis and Brain Development Laboratory, Division of Basic Neuroscience, McLean Hospital, Harvard Medical School, Belmont, Mass. 13. Division of Transplant Surgery and Transplantation Surgery Research Laboratory, Brigham and Women's Hospital, Harvard Medical School, Boston, Mass. Electronic address: aelkhal@partners.org.
Abstract
BACKGROUND: Given their unique capacity for antigen uptake, processing, and presentation, antigen-presenting cells (APCs) are critical for initiating and regulating innate and adaptive immune responses. We have previously shown the role of nicotinamide adenine dinucleotide (NAD+) in T-cell differentiation independently of the cytokine milieu, whereas the precise mechanisms remained unknown. OBJECTIVE: The objective of this study is to further dissect the mechanism of actions of NAD+ and determine the effect of APCs on NAD+-mediated T-cell activation. METHODS: Isolated dendritic cells and bone marrow-derived mast cells (MCs) were used to characterize the mechanisms of action of NAD+ on CD4+ T-cell fate in vitro. Furthermore, NAD+-mediated CD4+ T-cell differentiation was investigated in vivo by using wild-type C57BL/6, MC-/-, MHC class II-/-, Wiskott-Aldrich syndrome protein (WASP)-/-, 5C.C7 recombination-activating gene 2 (Rag2)-/-, and CD11b-DTR transgenic mice. Finally, we tested the physiologic effect of NAD+ on the systemic immune response in the context of Listeria monocytogenes infection. RESULTS: Our in vivo and in vitro findings indicate that after NAD+ administration, MCs exclusively promote CD4+ T-cell differentiation, both in the absence of antigen and independently of major APCs. Moreover, we found that MCs mediated CD4+ T-cell differentiation independently of MHC II and T-cell receptor signaling machinery. More importantly, although treatment with NAD+ resulted in decreased MHC II expression on CD11c+ cells, MC-mediated CD4+ T-cell differentiation rendered mice resistant to administration of lethal doses of L monocytogenes. CONCLUSIONS: Collectively, our study unravels a novel cellular and molecular pathway that regulates innate and adaptive immunity through MCs exclusively and underscores the therapeutic potential of NAD+ in the context of primary immunodeficiencies and antimicrobial resistance.
BACKGROUND: Given their unique capacity for antigen uptake, processing, and presentation, antigen-presenting cells (APCs) are critical for initiating and regulating innate and adaptive immune responses. We have previously shown the role of nicotinamide adenine dinucleotide (NAD+) in T-cell differentiation independently of the cytokine milieu, whereas the precise mechanisms remained unknown. OBJECTIVE: The objective of this study is to further dissect the mechanism of actions of NAD+ and determine the effect of APCs on NAD+-mediated T-cell activation. METHODS: Isolated dendritic cells and bone marrow-derived mast cells (MCs) were used to characterize the mechanisms of action of NAD+ on CD4+ T-cell fate in vitro. Furthermore, NAD+-mediated CD4+ T-cell differentiation was investigated in vivo by using wild-type C57BL/6, MC-/-, MHC class II-/-, Wiskott-Aldrich syndrome protein (WASP)-/-, 5C.C7 recombination-activating gene 2 (Rag2)-/-, and CD11b-DTR transgenic mice. Finally, we tested the physiologic effect of NAD+ on the systemic immune response in the context of Listeria monocytogenesinfection. RESULTS: Our in vivo and in vitro findings indicate that after NAD+ administration, MCs exclusively promote CD4+ T-cell differentiation, both in the absence of antigen and independently of major APCs. Moreover, we found that MCs mediated CD4+ T-cell differentiation independently of MHC II and T-cell receptor signaling machinery. More importantly, although treatment with NAD+ resulted in decreased MHC II expression on CD11c+ cells, MC-mediated CD4+ T-cell differentiation rendered mice resistant to administration of lethal doses of L monocytogenes. CONCLUSIONS: Collectively, our study unravels a novel cellular and molecular pathway that regulates innate and adaptive immunity through MCs exclusively and underscores the therapeutic potential of NAD+ in the context of primary immunodeficiencies and antimicrobial resistance.
Authors: Alexander Dobin; Carrie A Davis; Felix Schlesinger; Jorg Drenkow; Chris Zaleski; Sonali Jha; Philippe Batut; Mark Chaisson; Thomas R Gingeras Journal: Bioinformatics Date: 2012-10-25 Impact factor: 6.937
Authors: S B Snapper; F S Rosen; E Mizoguchi; P Cohen; W Khan; C H Liu; T L Hagemann; S P Kwan; R Ferrini; L Davidson; A K Bhan; F W Alt Journal: Immunity Date: 1998-07 Impact factor: 31.745
Authors: Stefan G Tullius; Hector Rodriguez Cetina Biefer; Suyan Li; Alexander J Trachtenberg; Karoline Edtinger; Markus Quante; Felix Krenzien; Hirofumi Uehara; Xiaoyong Yang; Haydn T Kissick; Winston P Kuo; Ionita Ghiran; Miguel A de la Fuente; Mohamed S Arredouani; Virginia Camacho; John C Tigges; Vasilis Toxavidis; Rachid El Fatimy; Brian D Smith; Anju Vasudevan; Abdallah ElKhal Journal: Nat Commun Date: 2014-10-07 Impact factor: 14.919