Chronic TNF-alpha exposure impairs TCR-signaling via TNF-RII but not TNF-RI.
Chronic exposure to TNF-alpha has been shown to impair T cell-activation in mice and in humans. In the present study, we investigated a possible role of TNF-RII in this long-term effect of TNF-alpha. Chronic TNF-alpha exposure led to suppression of subsequent TCR stimulation (e.g., TCR/CD28-induced proliferation, cytokine production (IFN-gamma, TNF-alpha)) but left TCR independent restimulation unaffected. Activation of T cells during TNF-alpha exposure was required for the inhibitory effect on TCR stimulation. In contrast to the mouse model, the inhibitory effect of long-term TNF-alpha exposure was mediated via TNF-RII but not TNF-receptor I, and surface expression of the TCR/CD3 complex remained unchanged. Chronic TNF-RII triggering downregulated T cell activation at an early level, as TCR-induced calcium flux and IL-2 mRNA expression were impaired after preculture in the presence of anti-TNF-RII mAbs. Furthermore, chronic TNF-RII-stimulation specifically downregulated store operated calcium channels, which contribute to sustained TCR-induced calcium influx.
Aspalter
Rosa M
RM
Immunology Outpatient Clinic, Schwarzspanierstrasse 15/9/1, A-1090 Vienna, Austria.
Wolf
Hermann M
HM
Eibl
Martha M
MM
D018106:CD28 Antigens / Q000276:immunology; D002118:Calcium / Q000378:metabolism; D015536:Down-Regulation; D005434:Flow Cytometry; D006801:Humans; D007376:Interleukin-2 / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology*; D011948:Receptors, Antigen, T-Cell / Q000276:immunology*; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000276:immunology*; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000276:immunology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000276:immunology*; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology* / Q000378:metabolism
D018106:CD28 Antigens; D007376:Interleukin-2; D011948:Receptors, Antigen, T-Cell; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; D014409:Tumor Necrosis Factor-alpha; D002118:Calcium