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 lymp hocyte 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, eve examined the effects of Moon- 1 and the anti-CD38 mAb IB4 on the effector functions of the IL-2-depe ndent T cell line TALL-104 (CD3/TCR-alpha beta(+), CD8(+), CD56(+)) an d 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 c ytotoxic CD8(+)/CD56(+) LAK subset was CD38L(+), Like mAb OKT3 (anti-C D3), and at variance with IB4, Moon-1 drastically enhanced the cytotox icity of TALL-104 and CD8(+) LAK cells against a resistant tumor targe t, Granule exocytosis did not appear to play a role in Moon-1-induced cytotoxicity. Moreover, neither IB4 nor Moon-1 induced [Ca2+](i) mobil ization in LAK and TALL-104 cells. Whereas stimulation of CD3 and CD38 resulted in a dramatic induction of cytokine (granulocyte-mncrophage- 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 i n TALL-104 tells, Thus, cytotoxicity and cytokine release are independ ently 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.