Stimulation of IFN-gamma, TNF-alpha, and TNF-beta 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-gamma (IFN-gamma). The NK subset of LAK (LAK-NK) cells is stimulated by tumor cells to secrete IFN-gamma in a non-MHC-restricted manner while the T cell subset of LAK (LAK-T) cells is stimulated to secrete IFN-gamma 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-alpha (TNF-alpha) and TNF-beta/lymphotoxin (TNF-beta). 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-gamma, TNF-alpha, and TNF-beta 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-gamma, TNF-alpha, and TNF-beta production by augmenting LAK-T cell to tumor cell adhesion and also by functioning as costimulators.
Department of General Surgery, Rush-Presbyterian-St. Luke's Medical Center, Chicago, Illinois 60612.
A S
AS
Chong
I A
IA
Boussy
L H
LH
Graf
P
P
Scuderi
D000911:Antibodies, Monoclonal; D000945:Antigens, Differentiation, T-Lymphocyte / Q000276:immunology*; D018801:CD2 Antigens; D017252:CD3 Complex / Q000276:immunology; D002448:Cell Adhesion / Q000187:drug effects / Q000276:immunology; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis*; D007376:Interleukin-2 / Q000494:pharmacology*; D015979:Killer Cells, Lymphokine-Activated / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D017493:Leukocyte Common Antigens / Q000276:immunology; D016169:Lymphocyte Function-Associated Antigen-1 / Q000276:immunology*; D008233:Lymphotoxin-alpha / Q000096:biosynthesis*; D011971:Receptors, Immunologic / Q000276:immunology*; D016201:Receptors, Lymphocyte Homing / Q000276:immunology; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*
D000911:Antibodies, Monoclonal; D000945:Antigens, Differentiation, T-Lymphocyte; D018801:CD2 Antigens; D017252:CD3 Complex; D007376:Interleukin-2; D016169:Lymphocyte Function-Associated Antigen-1; D008233:Lymphotoxin-alpha; D011971:Receptors, Immunologic; D016201:Receptors, Lymphocyte Homing; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; D017493:Leukocyte Common Antigens