Nonlymphocyte-Derived Tumor Necrosis Factor Is Required for Induction of Colitis in Recombination Activating Gene (Rag)2−/− Mice upon Transfer of Cd4+Cd45rbhi T Cells

In this study, we addressed the role of tumor necrosis factor (TNF)-alpha and lymphotoxin (LT)-alpha in the development of colitis and defined the cellular sources (T cells versus non-T cells) of TNF (TNF-alpha and LT-alpha) relevant to disease development. After adoptive transfer of TNF(+/+) CD4(+)CD45RB(hi) splenocytes into TNF(+/+) recombination activating gene (RAG)2(-/-) mice, the recipients develop massive inflammation of the large intestinal mucosa concurrent with massive weight loss. In contrast, clinical signs of disease are completely absent in TNF(-/-)RAG2(-/-) recipients of TNF(-/-) CD4(+)CD45RB(hi) T cells, although elevated numbers of interferon-gamma-producing cells are present in the colonic mucosa. Surprisingly, upon transfer of TNF(-/-)CD4(+)CD45RB(hi) T cells into TNF(+/+)RAG2(-/-) recipients, colitis develops with kinetics similar to those upon transfer of TNF(+/+)CD4(+)CD45RB(hi) donor cells. In contrast, no clinical signs of colitis are observed in TNF(-/-)RAG2(-/-) recipients of TNF(+/+)CD4(+)CD45RB(hi) T cells. This protection from colitis is not a consequence of the absence of LT-alpha, as TNF-alpha(-/-)RAG2(-/-) recipients of TNF-alpha(-/-) CD4(+)CD45RB(hi) T cells are also protected from colitis induction. These results demonstrate the importance of TNF production by non-T cells of the colonic mucosa in the pathogenesis of colitis and provide direct evidence for a nonredundant role of TNF-alpha in this mouse model of colitis.