Generation of an Inhibitory Circuit Involving CD8+ T Cells, IL-2, and NK Cell-Derived TGF-β: Contrasting Effects of Anti-CD2 and Anti-CD3

Abstract

Although the phenomenon of immunosuppression is well established, the mechanisms involved in the generation of lymphocytes with down-regulatory activity are poorly understood. Unlike anti-CD3 antibodies, mitogenic combinations of anti-CD2 antibodies do not stimulate human PBL to produce IgM or IgG. In determining the reason for this difference, we have found that anti-CD2 triggers an inhibitory circuit facilitated by TGF-β provided by NK cells. Stimulation of PBL with anti-CD2, but not anti-CD3, generated substantial amounts of active TGF-β. NK cells were found to be a significant source of TGF-β and were the only lymphocyte population that constitutively produced this cytokine. Anti-CD2 enhanced the production of active TGF-β by purified NK cells. TGF-β. After the removal of NK cells or the addition of anti-TGF-β, anti-CD2 could stimulate Ig production. Anti-TGF-β had to be added within the first 24 h for a maximal effect. Moreover, a short, overnight exposure of CD8+ T cells to TGF-β could prime them for suppressor activity provided that IL-2 was also present. Thus, the presence of active TGF-β coincident with CD8+ T cell activation can condition these cells to mediate down-regulatory activity, and NK cells can serve as the source of this cytokine.