Stimulation of IFN-γ, TNF-α, and TNF-β secretion in IL-2-activated T cells: Costimulatory roles for LFA-1, LFA-2, CD44, and CD45 molecules

Lymphokine-activated killer (LAK) cells are peripheral blood lymphocytes (PBLs) that possess the ability to kill target cells in a non-major histocompatibility complex (MHC)-restricted manner. Both NK and T cells can be stimulated with interleukin-2 (IL-2) to become LAK cells. We previously reported that the interaction of LAK cells with tumor cells also induces the secretion of interferon-γ (IFN-γ). The NK subset of LAK (LAK-NK) cells is stimulated by tumor cells to secrete IFN-γ in a non-MHC-restricted manner while the T cell subset of LAK (LAK-T) cells is stimulated to secrete IFN-γ upon cross-linking of the T cell receptor (TCR)-CD3 complex. We here report that LAK-T cells stimulated with anti-CD3 mAbs and tumor cells secrete two additional cytokines, tumor necrosis factor-α (TNF-α) and TNF-β/lymphotoxin (TNF-β). In addition, we demonstrate that at least four other structurally unrelated molecules, in addition to the TCR-CD3 complex, on LAK-T cells participate in the stimulation of IFN-γ, TNF-α, and TNF-β production. These molecules are the lymphocyte function associated antigen-1 (LFA-1), lymphocyte function associated antigen-2 (LFA-2), CD44, and CD45. LFA-1 is an integrin, LFA-2 is a member of the immunoglobulin supergene family, CD44 is homologous to the cartilage link proteins, and CD45 is a tyrosine phosphatase. Ligands to three of these molecules have been identified; ICAM-1. LFA-3, and hyaluronic acid binding to LFA-1, LFA-2, and CD44, respectively. LFA-1, LFA-2, and CD44 are reported to function both as adhesion molecules and as costimulators in resting T cells. Our data suggest that these three molecules enhance IFN-γ, TNF-α, and TNF-β production by augmenting LAK-T cell to tumor cell adhesion and also by functioning as costimulators.