CD30 signals integrate expression of cytotoxic effector molecules, lymphocyte trafficking signals, and signals for proliferation and apoptosis.
Although CD30 has long been recognized as an important marker on many lymphomas of diverse origin and as activation molecule on B cells and T cells, its primary function has remained obscure. We now report that CD30 signals may serve to inhibit effector cell activity by integrating gene expression changes of several pathways important for cytotoxic NK and T cell effector function. In the large granular lymphoma line YT, CD30 signals down-regulate the expression of cytotoxic effector molecules, Fas ligand, perforin, granzyme B, and abrogate cytotoxicity. c-myc, a regulator of proliferation and an upstream regulator of Fas ligand expression, is completely suppressed by CD30. Furthermore, CD30 signals strongly induce CCR7, suggesting a role for CD30 signals in the homing of lymphocytes to lymph nodes. The up-regulation of Fas, death receptor 3, and TNF-related apoptosis-inducing ligand by CD30 indicates an increase in susceptibility to apoptotic signals whereas up-regulation of TNFR-associated factor 1 and cellular inhibitor of apoptosis 2 protect cells from certain types of apoptosis. Using gene microarrays, 750 gene products were induced and 90 gene products were suppressed >2-fold by CD30 signals. Signals emanating from CD30 use both TNFR-associated factor 2-dependent and -independent pathways. The integration of CD30 signals in a lymphoma line suggests that CD30 can down-modulate lymphocyte effector function and proliferation while directing the cells to lymph nodes and increasing their susceptibility to certain apoptotic signals. These studies may provide a molecular mechanism for the recently observed CD30-mediated suppression of CTL activity in vivo in a diabetes model.
Muta
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H
Department of Microbiology and Immunology, University of Miami School of Medicine, Miami, FL 33136, USA.
Boise
L H
LH
Fang
L
L
Podack
E R
ER
D017209:Apoptosis / Q000276:immunology*; D051017:Apoptosis Regulatory Proteins; D002455:Cell Division / Q000276:immunology; D002460:Cell Line; D002465:Cell Movement / Q000276:immunology*; D003602:Cytotoxicity, Immunologic; D015536:Down-Regulation / Q000276:immunology; D053222:Fas Ligand Protein; D053804:Granzymes; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D017730:Ki-1 Antigen / Q000502:physiology*; D008024:Ligands; D016131:Lymphocyte Subsets / Q000166:cytology* / Q000276:immunology*; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism; D054353:Perforin; D052899:Pore Forming Cytotoxic Proteins; D014176:Protein Biosynthesis; D011506:Proteins / Q000502:physiology; D016271:Proto-Oncogene Proteins c-myc / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D054400:Receptors, CCR7; D019707:Receptors, Chemokine / Q000096:biosynthesis; D012697:Serine Endopeptidases / Q000096:biosynthesis; D015842:Serine Proteinase Inhibitors / Q000502:physiology; D015398:Signal Transduction / Q000276:immunology*; D047990:TNF Receptor-Associated Factor 1; D047992:TNF Receptor-Associated Factor 2; D053221:TNF-Related Apoptosis-Inducing Ligand; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000378:metabolism; D015854:Up-Regulation / Q000276:immunology; D019014:fas Receptor / Q000096:biosynthesis / Q000378:metabolism
D051017:Apoptosis Regulatory Proteins; C515370:CCR7 protein, human; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D051034:Inhibitor of Apoptosis Proteins; D017730:Ki-1 Antigen; D008024:Ligands; D008562:Membrane Glycoproteins; D052899:Pore Forming Cytotoxic Proteins; D011506:Proteins; D016271:Proto-Oncogene Proteins c-myc; D054400:Receptors, CCR7; D019707:Receptors, Chemokine; D015842:Serine Proteinase Inhibitors; D047990:TNF Receptor-Associated Factor 1; D047992:TNF Receptor-Associated Factor 2; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D014409:Tumor Necrosis Factor-alpha; D019014:fas Receptor; D054353:Perforin; C509213:GZMB protein, human; D053804:Granzymes; D012697:Serine Endopeptidases