An inhibitor of cytotoxic functions produced by CD8⁺CD57⁺ T lymphocytes from patients suffering from AIDS and immunosuppressed bone marrow recipients

Abstract

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.

CD57+/CD28− T cells in untreated hemato-oncological patients are expanded and display a Th1-type cytokine secretion profile, ex vivo cytolytic activity and enhanced tendency to apoptosis

“…Relevant to the latter possibility, regulatory or suppressive functions by CD8 + CD57 + /CD28 − T cells have been described by several groups. [8][9][10][34][35][36] In HIV-infected subjects CD8 + CD57 + /CD28 − T cells were shown to contain suppressors of cell-mediated cytotoxicity 13,14 as well as cytotoxic effectors. 37 Further investigations are thus required to reveal whether CD8 + CD57 + /CD28 − T cells in hemato-oncological patients similarly contain functionally heterogeneous populations.…”

“…12 CD8 + CD57 + lymphocytes from bone marrow transplant and HIV-infected patients produce a 20-30 kDa concanavalin A-binding, soluble factor able to suppress lectin-driven proliferation and cell-mediated cytotoxicity. 13,14 CD4 + CD57 + lymphocytes from normal subjects do not express mRNA for interleukin-2 (IL-2), IL-4 and CD40 ligand under conditions where CD4 + CD57 − cells normally do so, 15 and CD4 + CD57 + lymphocytes from both normal subjects and cancer patients have a reduced capacity to support B cell activation/differentiation. 15,16 Recently, it has been demonstrated that almost all CD57 + T cells lack expression of the B7 counter-receptor CD28, 17 which is generally considered to be very important as a second signal receptor for T cell activation.…”

Leukemic CD3+ LGL share functional properties with their CD8+CD57+ cell counterpart expanded after BMT

“…19,29,35 Indeed NK-mediated lysis was undetectable when whole PBMC were used as effector cells, in contrast with the K562 and Daudi lysis observed when testing sorted CD8 + CD57 − cells. We tested the culture supernatants (SN) from sorted CD8 + CD57 + leukemic cells of three patients (AD, DC, DL) for their ability to inhibit a normal LAK cell-mediated lysis.…”

“…Avidin-conjugated magnetic beads (Immunotech) were coupled with biotinylated CD57 mAb as previously described. 19,35 Cell suspensions were added to these complexes and mixed gently for 45 min at 4°C and CD57 + cells isolated by applying a cobalt magnet (Dynal, Oslo, Norway). The CD57 positive and negative cell fractions contained Ͼ90% and Ͻ10% of CD8 hi+ CD57 + cells, respectively.…”

“…Supernatants (SN) were prepared as described 19,35 from immuno-bead purified CD8 + CD57 + (SN + ) and control CD57 − cells (SN − ). Bead-attached cells and control cells were resuspended at 5 × 10 6 cells/ml in serum-free culture medium (RPMI 1640 supplemented with 1 mm sodium-pyruvate, 2 mm l-glutamine), without stimulation and incubated for 4 and 18 h at 37°C.…”