Regulation of CD2-mediated human T cell activation: anti-CD8 monoclonal antibodies inhibit CD2-mediated rise in intracellular calcium.
The human CD8 glycoprotein regulates the function of cytotoxic T cells activated by antigenic peptide as well as via CD3 or CD2 mAbs. Activation of T cells by CD2 mAbs requires two mAbs directed against distinct CD2 epitopes and induces tyrosine phosphorylation, PI-PLC activity generating the second messengers, IP3 and DAG, and finally lymphokine secretion. We have investigated the role of the CD8 alpha molecule in CD2-mediated activation of human cytotoxic T cell clones and CD8+ resting T cells. CD8 alpha-specific mAb inhibited 60% of the allospecific cytotoxicity of the CD8+ clone against its target cell and 86% of the CD2-redirected killing against the HLA Class I-negative Daudi target cell. In addition, CD8 alpha-specific mAb inhibited CD2-mediated TNF alpha and IL2 secretion by the CD8+ clone. Furthermore, CD8 alpha-specific mAb inhibited the increase in intracellular ionized calcium mediated by CD2 mAbs in the CD8+ clone and in purified T cells. Since the [Ca2+]i recruitment from internal stores induced by CD2 mAbs was inhibited, the inhibitory effect induced by the CD8 alpha-specific mAb probably acts on the PI-PLC activation pathway. This inhibition mechanism involves neither a decrease in affinity of CD2 mAb for its target nor a decrease in CD2 cell surface expression or a rise in cAMP known as an inhibitor of the CD2-mediated PI-PLC activity. These results suggest that the inhibitory mechanism induced by the CD8 mAb may prevent the activation of the PI-PLC activity, probably through the CD8 alpha-associated protein tyrosine kinase p56lck.
Franco
M D
MD
Unité 119 de l'Institut National de la Santé et de la Recherche Medicale, Marseille, France.
Nunes
J
J
Lipcey
C
C
Lopez
M
M
Mawas
C
C
Olive
D
D
D000911:Antibodies, Monoclonal / Q000494:pharmacology; D000945:Antigens, Differentiation, T-Lymphocyte / Q000235:genetics / Q000276:immunology*; D018801:CD2 Antigens; D016827:CD8 Antigens / Q000276:immunology*; D002118:Calcium / Q000378:metabolism*; D002462:Cell Membrane / Q000276:immunology; D000242:Cyclic AMP / Q000378:metabolism; D015870:Gene Expression; D006801:Humans; D007376:Interleukin-2 / Q000378:metabolism; D008213:Lymphocyte Activation / Q000276:immunology*; D011971:Receptors, Immunologic / Q000235:genetics / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
D000911:Antibodies, Monoclonal; D000945:Antigens, Differentiation, T-Lymphocyte; D018801:CD2 Antigens; D016827:CD8 Antigens; D007376:Interleukin-2; D011971:Receptors, Immunologic; D014409:Tumor Necrosis Factor-alpha; D000242:Cyclic AMP; D002118:Calcium