Mast Cells Regulate CD4+ T Cell Differentiation in Absence of Antigen Presentation
Hector Rodriguez Cetina Biefer1,2, Timm Heinbokel1, Hirofumi Uehara1,3, Virginia Camacho4, Suresh Koduru5, Rachid El Fatimy6, Ionita Ghiran7, Alexander J Trachtenberg8, Miguel A de la Fuente9, Haruhito Azuma3, Omid Akbari10, Anju Vasudevan11, Stefan G Tullius1, Abdallah Elkhal1.
1Division of Transplant Surgery and Transplantation Surgery Research Laboratory, Brigham and Women's Hospital, Boston, MA, United States; 2Clinic for Cardiovascular Surgery, University Hospital Zurich, Zurich, Switzerland; 3Department of Urology, Osaka Medical College, Osaka, Japan; 4Flow Cytometry Core Facility, Beth Israel Deaconess Medical Center, Harvard Stem Cell Institute, Boston, MA, United States; 5School of Medical Sciences, University of Hyderabad, Hyderabad, India; 6Department of Neurology, Center for Neurologic Diseases, Initiative for RNA Medicine, Brigham and Women’s Hospital, Boston, MA, United States; 7Department of Medicine, Beth Israel Deaconess Medical Center,, Boston, MA, United States; 8StART Families, Inc., Boston, MA, United States; 9Instituto de Biología y Genética Molecular, University of Valladolid, Valladolid, Spain; 10Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States; 11Angiogenesis and Brain Development Laboratory, Division of Basic Neuroscience, McLean Hospital, Belmont, MA, United States
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. Using bone marrow-derived mast cells and mast cell (MC) deficient mice, our in vivo and in vitro findings indicate that following NAD+ administration MCs, exclusively, promote CD4+ T-cell differentiation, both in absence of antigen and independently of major APCs. Moreover, we found that MCs mediated CD4+ T-cell differentiation independently of MHC-II and TCR signaling machinery. Although treatment with NAD+ resulted in a decreased MHC-II expression on CD11c+ cells, MC-mediated CD4+ T-cell differentiation rendered mice resistant to lethal doses of Listeria monocytogenes. Collectively, our study unravels a novel cellular and molecular pathway that regulates innate and adaptive immunity via MCs and may pave the way for novel therapeutic approaches in the context of immunodeficiencies and antimicrobial resistance.
