TNF plays a pivotal role in the pathogenesis of a broad spectrum of infectious, inflammatory, and autoimmune diseases. In addition to the secreted, mature 17 kD form, TNF exists as a bioactive precursor 26 kD transmembrane protein. Transmembrane TNF signaling has been directly associated with specific immune mechanisms, including the contact-dependent lymphocyte and monocyte-mediated cell killing and the CD40 ligand-independent, T cell-mediated polyclonal B cell activation. In previous studies, we have reported that mice expressing 3'-UTR modified human TNF transgenes develop chronic inflammatory polyarthritis with a 100% phenotypic penetrance and timed disease onset. In additional experiments, we have also shown that high-level expression of human TNF in lymphoid cells of transgenic mice results in both local (thymic hypoplasia) and systemic (ischaemia, tissue necrosis, and wasting) TNF-mediated pathology. In this study we show that transgenic mice expressing a T cell-targeted membrane-associated mutant human TNF alpha protein are displaying only local TNF-mediated pathologies, ranging from lymphoid tissue derangements to proliferative synovitis and chronic inflammatory arthritis. These results demonstrate that in vivo, at least part of the pathogenic activities of TNF alpha may be assigned to the functioning of its uncleaved, membrane-associated form.