Nonlymphocyte-Derived Tumor Necrosis Factor Is Required for Induction of Colitis in Recombination Activating Gene (Rag)2(−/−) Mice upon Transfer of Cd4(+)Cd45rb(hi) T Cells

In this study, we addressed the role of tumor necrosis factor (TNF)-α and lymphotoxin (LT)-α in the development of colitis and defined the cellular sources (T cells versus non-T cells) of TNF (TNF-α and LT-α) 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-γ–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-α, as TNF-α(−/−)RAG2(−/−) recipients of TNF-α(−/−) 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-α in this mouse model of colitis.