Monoclonal antibodies anti-CD3, anti-TCR alpha beta and anti-CD2 act synergistically with tumor cells to stimulate lymphokine-activated killer cells and tumor-infiltrating lymphocytes to secrete interferon gamma.
Peripheral blood lymphocytes cultured in interleukin-2 IL-2 acquire the ability to recognize and kill a wide range of tumor cells. Such promiscuous killer cells are termed lymphokine-activated killer (LAK) cells. We recently reported that the interaction of LAK cells with tumor cells stimulated the LAK cells to release interferon (IFN) gamma. Here, we report that the release of IFN gamma by LAK cells can be further enhanced by addition of the monoclonal antibodies (mAbs), anti-CD3, anti-(T cell receptor alpha beta) (TCR alpha beta) and a mitogenic combination of anti-CD2 (T112 + T113). Other antibodies, including a non-mitogenic anti-CD2 mAb (Leu5b), that recognize T cell-associated antigens were not stimulatory. The same stimulatory mAbs also synergized with tumor cells to stimulate tumor-infiltrating lymphocytes (TIL) to secrete IFN gamma. Additional experiments indicated that it was the T cell subset of LAK cells (LAK-T cells) that was stimulated by tumor cells and mAbs to release IFN gamma. Inhibition studies with specific mAbs suggest that the stimulation of IFN gamma release by LAK-T cells was dependent both on the aggregation of TCR-CD3 complexes on the LAK-T cell, and on the interaction of accessory molecules with their ligands. The accessory molecules we have identified as critical are LFA 1 and CD2/LFA-2 on LAK-T cells interacting with their respective ligands ICAM-1 and LFA3. Thus our data suggest that cytokine production in LAK-T cells can be regulated by multiple molecular interactions, involving the TCR-CD3 complex and adhesion molecules.
Chong
A S
AS
Department of General Surgery, Rush-Presbyterian-St. Luke's Medical Center, Chicago, IL 60612.
Staren
E D
ED
Scuderi
P
P
D000911:Antibodies, Monoclonal / Q000502:physiology*; D015703:Antigens, CD / Q000502:physiology; D000945:Antigens, Differentiation, T-Lymphocyte / Q000502:physiology*; D018801:CD2 Antigens; D017252:CD3 Complex / Q000502:physiology*; D018968:CD58 Antigens; D015815:Cell Adhesion Molecules / Q000502:physiology; D003602:Cytotoxicity, Immunologic; D006801:Humans; D018799:Intercellular Adhesion Molecule-1; D007371:Interferon-gamma / Q000378:metabolism*; D015979:Killer Cells, Lymphokine-Activated / Q000378:metabolism*; D004915:Leukemia, Erythroblastic, Acute / Q000503:physiopathology; D016169:Lymphocyte Function-Associated Antigen-1 / Q000502:physiology; D016246:Lymphocytes, Tumor-Infiltrating / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000502:physiology; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000502:physiology*; D017452:Receptors, IgG / Q000502:physiology; D011971:Receptors, Immunologic / Q000502:physiology*
D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D018801:CD2 Antigens; D017252:CD3 Complex; D018968:CD58 Antigens; D015815:Cell Adhesion Molecules; D016169:Lymphocyte Function-Associated Antigen-1; D008562:Membrane Glycoproteins; D016693:Receptors, Antigen, T-Cell, alpha-beta; D017452:Receptors, IgG; D011971:Receptors, Immunologic; D018799:Intercellular Adhesion Molecule-1; D007371:Interferon-gamma