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)‐γ. 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‐γ 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.

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