A T helper cell type 1–mediated colitis develops in severe combined immunodeficient mice after transfer of CD45RBhigh CD4+ T cells and can be prevented by cotransfer of the CD45RBlow subset. The immune-suppressive activities of the CD45RBlow T cell population can be reversed in vivo by administration of an anti-transforming growth factor β antibody. Here we show that interleukin (IL)-10 is an essential mediator of the regulatory functions of the CD45RBlow population. This population isolated from IL-10–deficient (IL-10−/−) mice was unable to protect from colitis and when transferred alone to immune-deficient recipients induced colitis. Treatment with an anti–murine IL-10 receptor monoclonal antibody abrogated inhibition of colitis mediated by wild-type (WT) CD45RBlow CD4+ cells, suggesting that IL-10 was necessary for the effector function of the regulatory T cell population. Inhibition of colitis by WT regulatory T cells was not dependent on IL-10 production by progeny of the CD45RBhigh CD4+ cells, as CD45RBlow CD4+ cells from WT mice were able to inhibit colitis induced by IL-10−/− CD45RBhigh CD4+ cells. These findings provide the first clear evidence that IL-10 plays a nonredundant role in the functioning of regulatory T cells that control inflammatory responses towards intestinal antigens.

We have characterized a cytokine produced by Th2 cells, designated as IL-25. Infusion of mice with IL-25 induced IL-4, IL-5, and IL-13 gene expression. The induction of these cytokines resulted in Th2-like responses marked by increased serum IgE, IgG(1), and IgA levels, blood eosinophilia, and pathological changes in the lungs and digestive tract that included eosinophilic infiltrates, increased mucus production, and epithelial cell hyperplasia/hypertrophy. In addition, our studies show that IL-25 induces Th2-type cytokine production by accessory cells that are MHC class II(high), CD11c(dull), and lineage(-). These results suggest that IL-25, derived from Th2 T cells, is capable of amplifying allergic type inflammatory responses by its actions on other cell types.

We have characterized the progressive stages of chronic intestinal inflammation that develops spontaneously in specific pathogen-free (SPF) mice with a targeted disruption in the IL-10 gene (IL-10 Ϫ / Ϫ ). Our longitudinal studies showed that inflammatory changes first appear in the cecum, ascending and transverse colon of 3-wk-old mutants. As the disease progressed, lesions appeared in the remainder of the colon and in the rectum. Some aged IL-10 Ϫ / Ϫ mice also developed inflammation in the small intestine. Prolonged disease with transmural lesions and a high incidence of colorectal adenocarcinomas (60%) was observed in 6-mo-old mutants. Mechanistic studies have associated uncontrolled cytokine production by activated macrophages and CD4

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CD4+ T cells in the mouse can be subdivided into two fractions based on the level of expression of the CD45RB determinant. Previous studies have shown that these subsets are functionally distinct. We have further characterized the properties of these subpopulations in vivo by injecting them into C. B-17 scid mice. The animals restored with the CD45RBhighCD4+ T cell population developed a lethal wasting disease with severe mononuclear cell infiltrates into the colon and elevated levels of IFN-gamma mRNA. In contrast, animals restored with the reciprocal CD45RBlow subset or with unfractionated CD4+ T cells did not develop the wasting or colitis. Importantly, the co-transfer of the CD45RBlow population with the CD45RBhigh population prevented the wasting disease and colitis. These data indicate that important regulatory interactions occur between the CD45RBhigh and CD45RBlowCD4+ T cell subsets and that disruption of this mechanism has fatal consequences.

SummaryA T helper type 1 (Thl)-mediated colitis with similarities to inflammatory bowel disease in humans developed in severe combined immunodeficiency mice reconstituted with CD45R_B high CD4 + splenic T ceils and could be prevented by cotransfer ofCD45RB l~ CD4 + T cells. Inhibition of this Thl response by the CD45ILB l~ T cell population could be reversed in vivo by an anti-transforming growth factor (TGF) 13 antibody. Interleukin (IL) 4 was not required for either the differentiation or function of protective cells as CD45RB l~ CD4 + cells from IL-4-deficient mice were fully effective. These results identify a subpopulation of peripheral CD4 + cells and TGF-13 as critical components of the natural immune regulatory mechanism, which prevents the development of pathogenic Thl responses in the gut, and suggests that this immunoregulatory population is distinct from Th2 cells.

Human herpesvirus 8 (HHV8, also known as Kaposi's sarcoma [KS]-associated herpesvirus) has been implicated as an etiologic agent for KS, an angiogenic tumor composed of endothelial, inflammatory, and spindle cells. Here, we report that transgenic mice expressing the HHV8-encoded chemokine receptor (viral G protein–coupled receptor) within hematopoietic cells develop angioproliferative lesions in multiple organs that morphologically resemble KS lesions. These lesions are characterized by a spectrum of changes ranging from erythematous maculae to vascular tumors, by the presence of spindle and inflammatory cells, and by expression of vGPCR, CD34, and vascular endothelial growth factor. We conclude that vGPCR contributes to the development of the angioproliferative lesions observed in these mice and suggest that this chemokine receptor may play a role in the pathogenesis of KS in humans.

SummaryMice 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 ofimmunoglobulin-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 oflL-10 -/-mice. B-/-IL-10 -/-mice acquired a severe colitis analogous to that oflL-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 R.AG-2 -/-mice with colitis were predominantly otI~TCR+CD4 +, including a large proportion of CD4 § + cells. These cells were also CD45RB -/l~ and CD44 +, indicative of an activated/memory population. Individual populations of CD4+CD80~ -, CD4+CD8oe + and CD4-CD8ot + 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+CD8ot -and CD4+CD8r + populations, induced colitis in recipient mice. Interferon-',/, but little to no IL-4, was produced by CD4+CD8o~ -and CD4+CD8ot § 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 THl-type cll3TCtk + T cells expressing CD4 alone, or in combination with the CD8ct molecule.