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)-alpha a nd lymphotoxin (LT)-alpha in the development of colitis and defined the cel lular sources (T cells versus non-T cells) of TNF (TNF-alpha and LT-alpha) relevant to disease development. After adoptive transfer of TNF+/+ CD4(+)CD 45RB(hi) splenocytes into TNF+/+ recombination activating gene (RAG)2(-/-) mice, the recipients develop massive inflammation of the large intestinal m ucosa concurrent with massive weight loss. In contrast, clinical signs of d isease are completely absent in TNF(-/-)RAG2(-/-) recipients of TNF-/- CD4( +)CD45RB(hi) T cells, although elevated numbers of interferon-gamma-produci ng cells are present in die 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(+)CD4 5RB(hi) donor cells. In contrast, no clinical signs of colitis are observed ill TNF(-/-)RAG2(-/-) recipients of TNF(+/+)CD4(+)CD45RB(hi) T cells. This protection from colitis is not a consequence of the absence of LT-alpha. a s TNF-alpha(-/-)RAG2(-/-) recipients of TNF-alpha(-/-) CD4(+)CD45RB(hi) T c ells are also protected from colitis induction. These results demonstrate t he importance of TNF production by non-T cells of die colonic mucosa in the pathogenesis of colitis and provide direct evidence for a nonredundant rol e of TNF-alpha ill this mouse model of colitis.