Tumor necrosis factor selectively inhibits activation of human B cells by Epstein-Barr virus

We have investigated the effect of recombinant human tumor necrosis factor-alpha (rTNF-alpha) on human B cell activation and differentiation. Among several T cell-dependent and independent B cell stimulation systems tested (anti-mu, pokeweed mitogen, Epstein-Barr virus), only the activation by Epstein-Barr virus was inhibited by rTNF-alpha. rTNF-alpha inhibited in a dose-dependent manner both the proliferation and differentiation (Ig secretion) of Epstein-Barr virus-stimulated B cells when added at the beginning or within 48 hr of a 6 to 8-day culture period. Maximal suppression (80 to 95%) was found at rTNF-alpha concentrations of 10 to 50 ng/ml. Inhibition of B cell activation required the presence of significant numbers (25%) of plastic adherent macrophages within the B cell population. Suppression was not due to lysis of Epstein-Barr virus-infected B cells by rTNF-alpha-treated macrophages. As shown by double chamber experiments where macrophages and B cells were separated by a 0.45-micron membrane, macrophages elaborated factors in response to rTNF-alpha, which, alone or synergistically with rTNF-alpha, inhibited B cell activation. These factors were different from prostaglandin E2, interferon-alpha, and interleukin 1. We conclude that rTNF-alpha can dramatically modulate certain normal immune responses in vitro.