Microbiota-instructed regulatory T cell differentiation is mediated by a distinct ROR γ t + antigen presenting cell subset
Year: 2021
Type: preprint
Abstract: The mutualistic relationship of gut-resident microbiota and cells of the host immune system promotes homeostasis that ensures maintenance of the microbial community and of a poised, but largely non-aggressive, immune cell compartment 1, 2 . Consequences of disturbing this balance, by environmental or genetic factors, include proximal inflammatory conditions, like Crohn’s disease, and systemic illnesses, both metabolic and autoimmune. One of the means by which this equilibrium is achieved is through induction of both effector and suppressor or regulatory arms of the adaptive immune system. In mice, Helicobacter species induce regulatory (iTreg) and follicular helper (Tfh) T cells in the colon-draining mesenteric lymph nodes under homeostatic conditions, but can instead induce inflammatory Th17 cells when iTreg cells are compromised 3, 4 . How Helicobacter hepaticus and other gut bacteria direct T cells to adopt distinct functions remains poorly understood. Here, we investigated which cells and molecular components are required to convey the microbial instruction for the iTreg differentiation program. We found that antigen presentation by cells expressing ROR γ t, rather than by classical dendritic cells, was both required and sufficient for iTreg induction. These ROR γ t + cells, likely to be type 3 innate lymphoid cells (ILC3) and/or a recently-described population of Aire + cells termed Janus cells 5 , require the MHC class II antigen presentation machinery, the chemokine receptor CCR7, and α v integrin, which activates TGF-β, for iTreg cell differentiation. In the absence of any of these, instead of iTreg cells there was expansion of microbiota-specific pathogenic Th17 cells, which were induced by other antigen presenting cells (APCs) that did not require CCR7. Thus, intestinal commensal microbes and their products target multiple APCs with pre-determined features suited to directing appropriate T cell differentiation programs, rather than a common APC that they endow with appropriate functions. Our results illustrate the ability of microbiota to exploit specialized functions of distinct innate immune system cells, targeting them to achieve the desired composition of equipoised T cells, thus maintaining tolerance.
Authors: Ranit Kedmi, Tariq Najar, Kailin R. Mesa, Allyssa Grayson, Lina Kroehling, Yuhan Hao, Stephanie Hao, Maria Pokrovskii, Mo Xu, Jhimmy Talbot, Jiaxi Wang, Joe Germino, Caleb A. Lareau, Ansuman T. Satpathy, Mark S. Anderson, Terri M. Laufer, Iannis Aifantis, Juliet M. Bartleson, Paul M. Allen, Helena Paidassi, James M. Gardner, Marlon Stoeckius, Dan R. Littman
Institutions: New York University, Howard Hughes Medical Institute, New York Genome Center, Calico Life Sciences, National Institute of Biological Sciences, Beijing, Fred Hutch Cancer Center, University of California, San Francisco, Parker Institute for Cancer Immunotherapy, Stanford University, Philadelphia VA Medical Center, University of Pennsylvania, Buck Institute for Research on Aging, Washington University in St. Louis, Lyon 1 Université, École Normale Supérieure de Lyon, Centre National de la Recherche Scientifique, Inserm, Centre International de Recherche en Infectiologie, 10X Genomics (Sweden)
Language: English
Topic: T-cell and B-cell Immunology
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: green
Funder: NYU Langone Medical Center
OpenAlex ID: W3214833245