title: Microbiota innate stimulation is a prerequisite for T cell spontaneous proliferation and induction of experimental colitis.
abstract: Little is known about how the microbiota regulates T cell proliferation and whether spontaneous T cell proliferation is involved in the pathogenesis of inflammatory bowel disease. In this study, we show that stimulation of innate pathways by microbiota-derived ligands and antigen-specific T cell stimulation are both required for intestinal inflammation. Microbiota-derived ligands promoted spontaneous T cell proliferation by activating dendritic cells (DCs) to produce IL-6 via Myd88, as shown by the spontaneous proliferation of T cells adoptively transferred into specific pathogen-free (SPF) RAG-/- mice, but not in germfree RAG-/- mice. Reconstitution of germfree RAG-/- mice with cecal bacterial lysate-pulsed DCs, but not with IL-6-/- or Myd88-/- DCs, restored spontaneous T cell proliferation. CBir1 TCR transgenic (CBir1 Tg) T cells, which are specific for an immunodominant microbiota antigen, induced colitis in SPF RAG-/- mice. Blocking the spontaneous proliferation of CBir1 Tg T cells by co-transferring bulk OT II CD4+ T cells abrogated colitis development. Although transferred OT II T cells underwent spontaneous proliferation in RAG-/- mice, the recipients failed to develop colitis because of the lack of cognate antigen in the intestinal lumen. Collectively, our data demonstrate that induction of colitis requires both spontaneous proliferation of T cells driven by microbiota-derived innate signals and antigen-specific T cell proliferation.
authors.affiliation: Department of Microbiology, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
authors.forename: Ting
authors.initials: T
authors.lastname: Feng
authors.forename: Lanfang
authors.initials: L
authors.lastname: Wang
authors.forename: Trenton R
authors.initials: TR
authors.lastname: Schoeb
authors.forename: Charles O
authors.initials: CO
authors.lastname: Elson
authors.forename: Yingzi
authors.initials: Y
authors.lastname: Cong
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000494:pharmacology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology*; D002452:Cell Count; D049109:Cell Proliferation / Q000187:drug effects; D003092:Colitis / Q000139:chemically induced / Q000276:immunology* / Q000382:microbiology* / Q000473:pathology; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology; D005408:Flagellin / Q000276:immunology; D018398:Homeodomain Proteins / Q000378:metabolism; D007113:Immunity, Innate / Q000187:drug effects / Q000276:immunology*; D015850:Interleukin-6 / Q000096:biosynthesis; D054892:Metagenome / Q000187:drug effects / Q000276:immunology*; D051379:Mice; D008822:Mice, Transgenic; D018448:Models, Immunological; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D019947:Receptors, Interleukin-6 / Q000276:immunology; D013047:Specific Pathogen-Free Organisms / Q000276:immunology
chemical_list: D000911:Antibodies, Monoclonal; C502160:CBir1 flagellin; D018398:Homeodomain Proteins; D015850:Interleukin-6; D053594:Myeloid Differentiation Factor 88; D011948:Receptors, Antigen, T-Cell; D019947:Receptors, Interleukin-6; D005408:Flagellin; C064658:RAG-1 protein