Chronic Tumor Necrosis Factor Alters T Cell Responses by Attenuating T Cell Receptor Signaling

Abstract

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.

Tumor Necrosis Factor Blockade in Chronic Murine Tuberculosis Enhances Granulomatous Inflammation and Disorganizes Granulomas in the Lungs

“…A protective anti-inflammatory effect of TNF has also been described for the murine nonobese diabetes model (9). With the use of an influenza hemagglutinin transgenic T-cell receptor mouse model, TNF has been shown to suppress a broad range of T-cell responses, including IFN-␥ production (9). This in vivo observation of the IFN-␥-attenuating attribute of TNF was recapitulated in an in vitro model of chronic TNF exposure (9).…”

“…In addition, it has been reported that TNF mediates a tissue-damaging effect in the acute phase of inflammation in the mouse experimental allergic encephalomyelitis model while exerting an immunosuppressive effect as the disease progresses, which eventually leads to protection against tissue damage and remission (18,19). A protective anti-inflammatory effect of TNF has also been described for the murine nonobese diabetes model (9). With the use of an influenza hemagglutinin transgenic T-cell receptor mouse model, TNF has been shown to suppress a broad range of T-cell responses, including IFN-␥ production (9).…”

Endogenous HLA–DR–restricted presentation of the cartilage antigens human cartilage gp‐39 and melanoma inhibitory activity in the inflamed rheumatoid joint

“…In healthy individuals these cells may have a role in preserving natural immune homeostasis, a function that is suppressed in RA (42). However, so far, the presence of functional HC gp-39-specific T cells in SF has been difficult to detect, possibly due to local T cell exhaustion or suppression (37)(38)(39)(40)42,43).…”

Soluble TNF‐α but not transmembrane TNF‐α sensitizes T cells for enhanced activation‐induced cell death

“…Exposure of T cells to TNF, in particular during chronic inflammatory conditions, has been reported to exert antiinflammatory effects on T cells, in particular by attenuating TCRmediated signaling and proliferative expansion [13]. Prolonged exposure to TNF in vitro leads to hyporesponsiveness of T cells [14] possibly by uncoupling proximal [15] as well as distal [16] TCR signals, thus indicating an important and direct immunomodulatory function of TNF on activated T cells.…”