Role of CD38 and its ligand in the regulation of MHC-nonrestricted cytotoxic T cells.
Human CD38 is a type II transmembrane glycoprotein that regulates lymphocyte adhesion, proliferation, and cytokine production. The mAb Moon-1 recognizes a ligand for CD38 (CD38L) and specifically inhibits CD38-mediated cell adhesion. To analyze the role of CD38 and its ligand in MHC-nonrestricted T cell activation, we examined the effects of Moon-1 and the anti-CD38 mAb IB4 on the effector functions of the IL-2-dependent T cell line TALL-104 (CD3/TCR-alphabeta+, CD8+, CD56+) and of LAK cells (90% CD3+). TALL-104 cells were almost 100% reactive with both mAbs, whereas the reactivity of LAK cells for IB4 and Moon-1 ranged from 10 to 60% among different donors. From 78 to 94% of the cytotoxic CD8+/CD56+ LAK subset was CD38L+. Like mAb OKT3 (anti-CD3), and at variance with IB4, Moon-1 drastically enhanced the cytotoxicity of TALL-104 and CD8+ LAK cells against a resistant tumor target. Granule exocytosis did not appear to play a role in Moon-1-induced cytotoxicity. Moreover, neither IB4 nor Moon-1 induced [Ca2+]i mobilization in LAK and TALL-104 cells. Whereas stimulation of CD3 and CD38 resulted in a dramatic induction of cytokine (granulocyte-macrophage-CSF, IFN-gamma, TNF-alpha, and TNF-beta) release by both TALL-104 and LAK cells, ligation of CD38L was not followed by cytokine production in TALL-104 cells. Thus, cytotoxicity and cytokine release are independently regulated, at least in this system. These data demonstrate that CD38 and its ligand can regulate some T cell functions using signaling pathways distinct from those of CD3.
Cesano
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A
The Wistar Institute of Anatomy and Biology, Philadelphia, PA 19104, USA.
Visonneau
S
S
Deaglio
S
S
Malavasi
F
F
Santoli
D
D
D036541:ADP-ribosyl Cyclase; D051997:ADP-ribosyl Cyclase 1; D000818:Animals; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000096:biosynthesis / Q000378:metabolism / Q000502:physiology*; D002118:Calcium / Q000378:metabolism; D015550:Cell Degranulation / Q000276:immunology; D002460:Cell Line; D003602:Cytotoxicity, Immunologic; D006801:Humans; D007424:Intracellular Fluid / Q000378:metabolism; D015979:Killer Cells, Lymphokine-Activated / Q000276:immunology / Q000378:metabolism; D008024:Ligands; D008213:Lymphocyte Activation; D008285:Major Histocompatibility Complex / Q000276:immunology*; D008562:Membrane Glycoproteins; D051379:Mice; D009244:NAD+ Nucleosidase / Q000096:biosynthesis / Q000378:metabolism / Q000502:physiology*; D011485:Protein Binding / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000378:metabolism; D014407:Tumor Cells, Cultured
D015703:Antigens, CD; D000943:Antigens, Differentiation; D008024:Ligands; D008562:Membrane Glycoproteins; D036541:ADP-ribosyl Cyclase; C498154:CD38 protein, human; C498155:Cd38 protein, mouse; D009244:NAD+ Nucleosidase; D051997:ADP-ribosyl Cyclase 1; D002118:Calcium