TY - JOUR
T1 - Chronic tumor necrosis factor alters T cell responses by attenuating T cell receptor signaling
AU - Cope, Andrew P.
AU - Liblau, Roland S.
AU - Yang, Xiao Dong
AU - Congia, Mauro
AU - Laudanna, Carlo
AU - Schreiber, Robert D.
AU - Probert, Lesley
AU - Kollias, George
AU - McDevitt, Hugh O.
PY - 1997/5/5
Y1 - 1997/5/5
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=0030911341&partnerID=8YFLogxK
U2 - 10.1084/jem.185.9.1573
DO - 10.1084/jem.185.9.1573
M3 - Article
C2 - 9151895
AN - SCOPUS:0030911341
SN - 0022-1007
VL - 185
SP - 1573
EP - 1584
JO - Journal of Experimental Medicine
JF - Journal of Experimental Medicine
IS - 9
ER -