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) the 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 of 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 αβTCR+CD4+, including a large proportion of CD4+CD8α+ cells. These cells were also CD45RB(-/low) and CD44+, indicative of an activated/memory population. Individual populations of CD4+CD8α-, CD4+CD8α+ and CD4-CD8α+ 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+CD8α- and CD4+CD8α+ populations, induced colitis in recipient mice. Interferon-γ, but little to no IL-4, was produced by CD4+CD8α- and CD4+CD8α+ LPL recovered from the inflamed colons of RAG- 2(-/-) recipients implicating a T helper cell 1 (TH1)-mediated response. We thus conclude that colitis in IL-10(-/-) mice is predominantly mediated by TH1-type αβTCR+ T cells expressing CD4 alone, or in combination with the CD8α molecule.