Human T cells from autoimmune and normal individuals can produce tumor necrosis factor

Abstract

T cell clones derived from patients with autoimmune diseases were found to be capable of producing tumor necrosis factor (TNF). This was demonstrated by stimulating the clones, in the absence of accessory cells, with antibodies against the Ti/T3 complex and with recombinant interleukin 2 (IL2). Analysis of RNA extracted from these clones showed that TNF mRNA was more abundant than lymphotoxin (LT) mRNA. We also found that TNF protein in the supernatants of these clones was generally more abundant than LT as assessed by using the murine L929 cell assay. TNF production was not limited to T cells from autoimmune individuals, since the T cell tumor HUT78 and T cells purified from the peripheral blood of healthy individuals also made TNF. Unlike the T cell clones, HUT78 produced greater amounts of LT mRNA than TNF mRNA. Induction of TNF mRNA in T cells from healthy individuals displayed a two-signal requirement (phorbol myristate 13-acetate and phytohemagglutinin or OKT3 and phorbol myristate 13-acetate), similar to that described for the induction of the T cell lymphokines IL 2 and interferon-gamma (IFN-gamma). Additionally we found that IL2 alone was sufficient to induce TNF in these cells when they had been precultured with phytohemagglutinin for 7 days to express IL 2 receptors. The cloned T cells we have characterized also produce IFN-gamma which was detected in the supernatants of the clones using a radioimmunoassay. The evidence suggests that T cells can produce TNF and have the potential to deliver by themselves the dual and synergistic signals of TNF/LT and IFN-gamma to target cells, a process which may be of importance in the pathogenesis of human autoimmunity.

IDO-Independent Suppression of T Cell Effector Function by IFN-γ–Licensed Human Mesenchymal Stromal Cells

“…By considering the combinatorial IFN-g-licensed direct effect of MSCs on T cell proliferation, effector function, and the indirect effect on T cell proliferation through soluble factors, we predict that IFN-g-prelicensed autologous MSCs would generate a more potent and primed cell therapy product for suppression of immune ailments (61). The inhibitory potential of IFN-g-licensed MSCs on the highly inflammatory TNF-a + -producing T cells we observed is of significant interest because this T cell effector subset may be associated with the pathogenesis of autoimmune disorders amenable to MSC cellular therapies (62).…”

Chronic exposure to tumor necrosis factor (TNF) in vitro impairs the activation of T cells through the T cell receptor/CD3 complex; reversal in vivo by anti-TNF antibodies in patients with rheumatoid arthritis.

“…Since bioactive TNF is detectable in synovial joint cell cultures, as well as in synovial fluid (21), it is likely that synovial joint T cells overexpressing TNF-R are persistently exposed to TNF in vivo. These characteristics are similar to T cell lines or clones, which, when cultured in vitro for prolonged periods, are chronically activated, secrete abundant TNF (31), and express high levels of TNF-R (32, and A. Cope, unpublished data).…”

Localization of Tumor Necrosis Factor α in Synovial Tissues and at the Cartilage–Pannus Junction in Patients With Rheumatoid Arthritis

“…After stimulation of peripheral blood lymphocytes with endotoxin in vitro (33), the macrophages are the major source of TNFa, but T cells can also secrete TNFa (19,20). Our results show that cells of the monocyte/macrophage lineage are the major source of TNFa in RA synovial membrane, but 2.5% of T cells also contained TNFa.…”