Chronic tumor necrosis factor alters T cell responses by attenuating T cell receptor signaling

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

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245 Scopus citations


Repeated injections of adult mice with recombinant murine TNF prolong the survival of NZB/W F1 mice, and suppress type 1 insulin-dependent diabetes mellitus (IDDM) in non-obese 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.

Original languageEnglish
Pages (from-to)1573-1584
Number of pages12
JournalJournal of Experimental Medicine
Issue number9
StatePublished - May 5 1997

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    Cope, A. P., Liblau, R. S., Yang, X. D., Congia, M., Laudanna, C., Schreiber, R. D., Probert, L., Kollias, G., & McDevitt, H. O. (1997). Chronic tumor necrosis factor alters T cell responses by attenuating T cell receptor signaling. Journal of Experimental Medicine, 185(9), 1573-1584.