Generation of an inhibitory circuit involving CD8+ T cells, IL-2, and NK cell-derived TGF-beta: contrasting effects of anti-CD2 and anti-CD3.
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-beta provided by NK cells. Stimulation of PBL with anti-CD2, but not anti-CD3, generated substantial amounts of active TGF-beta. NK cells were found to be a significant source of TGF-beta and were the only lymphocyte population that constitutively produced this cytokine. Anti-CD2 enhanced the production of active TGF-beta by purified NK cells. TGF-beta. After the removal of NK cells or the addition of anti-TGF-beta, anti-CD2 could stimulate Ig production. Anti-TGF-beta had to be added within the first 24 h for a maximal effect. Moreover, a short, overnight exposure of CD8+ T cells to TGF-beta could prime them for suppressor activity provided that IL-2 was also present. Thus, the presence of active TGF-beta 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.
Gray
J D
JD
Department of Medicine, University of Southern California School of Medicine, Los Angeles 90033, USA.
Hirokawa
M
M
Ohtsuka
K
K
Horwitz
D A
DA
D000328:Adult; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D018801:CD2 Antigens / Q000276:immunology*; D017252:CD3 Complex / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002460:Cell Line; D002478:Cells, Cultured; D003602:Cytotoxicity, Immunologic; D015536:Down-Regulation / Q000276:immunology*; D006801:Humans; D007074:Immunoglobulin G / Q000096:biosynthesis; D007075:Immunoglobulin M / Q000096:biosynthesis; D007376:Interleukin-2 / Q000502:physiology*; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism; D008213:Lymphocyte Activation; D008907:Mink; D016212:Transforming Growth Factor beta / Q000276:immunology / Q000502:physiology*
D000911:Antibodies, Monoclonal; D018801:CD2 Antigens; D017252:CD3 Complex; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D007376:Interleukin-2; D016212:Transforming Growth Factor beta