Interleukin-2 (IL-2) receptor alpha knockout (
IL-2Ralpha(-/-)) mice have a deficiency of CD25 and a corresponding functional defect in T regulatory cells (Tregs). These mice spontaneously develop portal
inflammation with biliary ductular damage and
colitis with features similar to human
inflammatory bowel disease with T cell infiltrates in both the liver and colon. In humans,
inflammatory bowel disease may be accompanied by
primary sclerosing cholangitis (PSC), but seldom
primary biliary cirrhosis (PBC). We hypothesized that the effector mechanism responsible for T cell infiltrates would differ for colon versus liver. To address this thesis, we developed three colonies of double-knockout mice including
IL-2Ralpha(-/-) CD4(-/-),
IL-2Ralpha(-/-) CD8(-/-), and
IL-2Ralpha(-/-)
T cell receptor (TCR)-beta(-/-). Tissue immunopathology,
body weight, and serum levels of
cytokines,
immunoglobulins, and anti-mitochondrial
antibodies (AMA) were assayed at 3 months of age. Relative to
IL-2Ralpha(-/-) mice,
IL-2Ralpha(-/-) CD4(-/-) mice had increased biliary ductular damage but reduced
inflammation in the colon. In contrast,
IL-2Ralpha(-/-) CD8(-/-) mice had increased colon
inflammation but markedly attenuated biliary ductular damage. Both
IL-2Ralpha(-/-) CD4(-/-) and
IL-2Ralpha(-/-) CD8(-/-) mice demonstrated elevated serum levels of
tumor necrosis factor alpha (
TNF-alpha),
interferon gamma (IFN-gamma), interleukin-12p40 (IL-12p40), and
interleukin-2 (IL-2) compared with C57BL/6J controls, but only
IL-2Ralpha(-/-) CD8(-/-) mice had increased serum levels of
immunoglobulin A (
IgA), AMA and
interleukin-17 (IL-17). Finally, and of importance,
IL-2Ralpha(-/-) TCR-beta(-/-) mice had abrogation of liver and colon pathological conditions and lacked AMA. In conclusion, on loss of Treg function in mice, CD8 T cells mediate biliary ductular damage whereas CD4 T cells mediate induction of colon-specific autoimmunity.