title: T helper cell 1-type CD4+ T cells, but not B cells, mediate colitis in interleukin 10-deficient mice.
abstract: Mice rendered deficient in the production of interleukin 10 (IL-10-/-) develop a chronic inflammatory bowel disease (IBD) that predominates in the colon and shares histopathological features with human IBD. Our aim was to identify which cell type(s) can mediate colitis in IL-10-/- mice. We detected an influx of immunoglobulin-positive cells into the colon and the presence of colon-reactive antibodies in the serum of IL-10-/- mice. To assess a pathogenic role for B cells, we generated a B cell-deficient (B-/-) strain of IL-10-/- mice. B-/-IL-10-/- mice acquired a severe colitis analogous to that IL-10-/- mice, implying that B cells were not the primary mediator of IBD in this model. A series of cell transfer experiments was performed to assess a pathogenic role for T cells. When IL-10-/- T cell-enriched lamina propria lymphocytes (LPL) or intraepithelial lymphocytes (IEL) were transferred into immunodeficient recombinase-activating gene (RAG)-2-/- recipients, a mild to severe colitis developed, depending on the cell number transferred. Lymphocytes recovered from the colon of transplanted RAG-2-/- mice with colitis were predominantly alpha beta TCR+CD4+, including a large proportion of CD4+CD8 alpha + cells. These cells were also CD45RB-/low and CD44+, indicative of an activated/memory population. Individual populations of CD4+CD8 alpha-, CD4+CD8 alpha + and CD4-CD8 alpha + T cells were then isolated from the lamina propria compartment of IL-10-/- mice and transferred into RAG-2-/- recipients. Only IL-10-/- CD4-expressing LPL, including both the CD4+CD8 alpha- and CD4+CD8 alpha + populations, induced colitis in recipient mice. Interferon-gamma, but little to no IL-4, was produced by CD4+CD8 alpha- and CD4+CD8 alpha + LPL recovered from the inflamed colons of RAG-2-/- recipients implicating alpha T helper cell 1 (TH1)-mediated response. We thus conclude that colitis in IL-10-/- mice is predominantly mediated by TH1-type alpha beta TCR+ T cells expressing CD4 alone, or in combination with the CD8 alpha molecule.
authors.affiliation: DNAX Research Institute of Molecular and Cellular Biology Inc., Palo Alto, California 94304, USA.
authors.forename: N J
authors.initials: NJ
authors.lastname: Davidson
authors.forename: M W
authors.initials: MW
authors.lastname: Leach
authors.forename: M M
authors.initials: MM
authors.lastname: Fort
authors.forename: L
authors.initials: L
authors.lastname: Thompson-Snipes
authors.forename: R
authors.initials: R
authors.lastname: Kühn
authors.forename: W
authors.initials: W
authors.lastname: Müller
authors.forename: D J
authors.initials: DJ
authors.lastname: Berg
authors.forename: D M
authors.initials: DM
authors.lastname: Rennick
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D003092:Colitis / Q000276:immunology*; D003106:Colon / Q000276:immunology; D016207:Cytokines / Q000096:biosynthesis; D004268:DNA-Binding Proteins; D007116:Immunization, Passive; D015212:Inflammatory Bowel Diseases / Q000235:genetics / Q000276:immunology*; D016753:Interleukin-10 / Q000172:deficiency; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011506:Proteins / Q000502:physiology; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000032:analysis; D016176:T-Lymphocyte Subsets / Q000276:immunology; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology*
chemical_list: D016207:Cytokines; D004268:DNA-Binding Proteins; D011506:Proteins; C499308:Rag2 protein, mouse; D016693:Receptors, Antigen, T-Cell, alpha-beta; C064655:V(D)J recombination activating protein 2; D016753:Interleukin-10