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Andrew P. Cope^*, Roland S. Liblau^*, Xiao-Dong Yang^*, Mauro Congia^*, Carlo Laudanna, Robert D. Schreiber^||, Lesley Probert^¶, George Kollias^¶, and Hugh O. McDevitt^*,

From the ^* Department of Microbiology and Immunology, Department of Pathology, and Department of Medicine, Stanford University School of Medicine, Stanford, California 94305; ^|| Department of Pathology, Washington University School of Medicine, St. Louis, Missouri 63110; and ^¶ Department of Molecular Genetics, Hellenic Pasteur Institute, Athens, Greece

Repeated injections of adult mice with recombinant murine TNF prolong the survival of NZB/W F1 mice, and suppress type I insulin-dependent diabetes mellitus (IDDM) in nonobese diabetic (NOD) mice. To determine whether repeated TNF injections suppress T cell function in adult mice, we studied the responses of influenza hemagglutinin-specific T cells derived from T cell receptor (HNT-TCR) transgenic mice. Treatment of adult mice with murine TNF for 3 wk suppressed a broad range of T cell responses, including proliferation and cytokine production. Furthermore, T cell responses of HNT-TCR transgenic mice also expressing the human TNF-globin transgene were markedly reduced compared to HNT-TCR single transgenic littermates, indicating that sustained p55 TNF-R signaling is sufficient to suppress T cell function in vivo. Using a model of chronic TNF exposure in vitro, we demonstrate that (a) chronic TNF effects are dose and time dependent, (b) TNF suppresses the responses of both Th1 and Th2 T helper subsets, (c) the suppressive effects of endogenous TNF produced in T cell cultures could be reversed with neutralizing monoclonal antibodies to TNF, and (d) prolonged TNF exposure attenuates T cell receptor signaling. The finding that anti-TNF treatment in vivo enhances T cell proliferative responses and cytokine production provides evidence for a novel regulatory effect of TNF on T cells in healthy laboratory mice. These effects are more pronounced in chronic inflammatory disease. In addition, our data provide a mechanism through which prolonged TNF exposure suppresses disease in animal models of autoimmunity.

¹ Abbreviations used in this paper: IDDM, insulin-dependent diabetes mellitus; NOD, non-obese diabetic; RA, rheumatoid arthritis.

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