T-HELPER CELL 1-TYPE CD4(-CELLS, BUT NOT B-CELLS, MEDIATE COLITIS IN INTERLEUKIN 10-DEFICIENT MICE() T)

Mice rendered deficient in the production of interleukin 10 (IL-10(-/- )) develop a chronic inflammatory bowel disease (IBD) that predominate s in the colon and shares histopathological features with human IBD. O ur aim was to identify which cell type(s) can mediate colitis in IL-10 (-/-) mice. We detected an influx of immunoglobulin-positive cells int o 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 gener ated a B cell-deficient (B--/-) strain of IL-10(-/-) mice. B(-/-)IL-10 (-/-) mice acquired a severe colitis analogous to that of IL-10(-/-) m ice, implying that B sells were not the primary mediator of IBD in thi s 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 trans planted RAG-2-(-/-) mice with colitis were predominantly of alpha beta TCR(+)CD4(+), including a large proportion of CD4(-)CD8 alpha(+) cell s. These cells were also CD45RB(-/low) and CD44(+), indicative of an a ctivated/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, inclu ding both the CD4(+)CD8 alpha(-) and CD4(+)CD8 alpha(+) populations, i nduced colitis in recipient mice. Interferon-gamma, but little to no I L-4, was produced by CD4(+)CD8 alpha(-) and CD4(+)CD8 alpha(+) LPL rec overed from the inflamed colons of RAG-2(-/-) recipients implicating a T helper cell 1 (TH1)-mediated response. We thus conclude that coliti s in IL-10(-/-) mice is predominantly mediated by TH1-type alpha beta TCR(+) T cells expressing CD4 alone, or in combination with the CD8 al pha molecule.