Original Article

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

Correspondence to: Christoph Mueller, Institute of Pathology, Div. of Immunopathology, Murtenstrasse 31, CH-3010 Bern, Switzerland. Tel:41-31-632-89-04 Fax:41-31-381-87-64 E-mail:christoph.mueller{at}pathology.unibe.ch.

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

Key Words: inflammatory bowel disease, mucosal immunity, intestinal inflammation, proinflammatory cytokines

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