An inhibitor of cytotoxic functions produced by CD8+CD57+ T lymphocytes from patients suffering from AIDS and immunosuppressed bone marrow recipients.
An inhibitor of the cytotoxic functions (ICF) mediated by human immunodeficiency virus (HIV)- or HLA-specific cytotoxic T lymphocytes, natural killer and lymphokine-activated killer (LAK) cells is secreted by CD8+CD57+ T lymphocytes, a subset expanded during infection with HIV and after bone marrow transplantation. We previously showed an apparent molecular mass of 20-30 kDa for this soluble glycosylated concanavalin A-binding inhibitor which is distinct from known cytokines. Here, we report a characterization of the mechanism of action of this CD8+CD57+ ICF. We show that the ICF-induced inhibition of LAK cell cytolytic activity is transient, with a spontaneous recovery of cytolytic potential after 18 h. When testing interactions of ICF with a large set of cytokines we found that the ICF-mediated inhibition of cytotoxic functions is antagonized by two cytokines: recombinant interleukin (rIL)-4 and recombinant interferon (rIFN)-gamma. Finally, we show that ICF acts at the level of cytolytic effector cells, where it induces a significant increase of cyclic AMP (cAMP) level. In contrast, no modification of either cell surface antigen expression or of target/effector cell conjugate formation could be evidenced. Addition of rIL-4 and rIFN-gamma reverses such an increase of cAMP levels and in parallel restores the cytolytic activity. Altogether, these data demonstrate that the glycoprotein ICF produced by CD8+CD57+ cells (1) inhibits cell-mediated cytotoxicity by sensitizing cytolytic effector cells to the cAMP pathway, and (2) is part of a cytokine network controlling cell-mediated cytotoxic functions.
Sadat-Sowti
B
B
Laboratoire d'Immunologie Cellulaire et Tissulaire, Paris, France.
Debré
P
P
Mollet
L
L
Quint
L
L
Hadida
F
F
Leblond
V
V
Bismuth
G
G
Autran
B
B
D000163:Acquired Immunodeficiency Syndrome / Q000276:immunology*; D015703:Antigens, CD / Q000032:analysis*; D000945:Antigens, Differentiation, T-Lymphocyte / Q000032:analysis*; D016026:Bone Marrow Transplantation; D018959:CD57 Antigens; D016827:CD8 Antigens / Q000032:analysis*; D000242:Cyclic AMP / Q000096:biosynthesis; D003602:Cytotoxicity, Immunologic / Q000187:drug effects*; D006023:Glycoproteins / Q000494:pharmacology*; D006801:Humans; D007108:Immune Tolerance; D007371:Interferon-gamma / Q000494:pharmacology; D015847:Interleukin-4 / Q000494:pharmacology; D011994:Recombinant Proteins / Q000494:pharmacology; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000502:physiology*
D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D018959:CD57 Antigens; D016827:CD8 Antigens; D006023:Glycoproteins; D011994:Recombinant Proteins; D015847:Interleukin-4; D007371:Interferon-gamma; D000242:Cyclic AMP