Transforming growth factor beta from multiple myeloma cells inhibits proliferation and IL-2 responsiveness in T lymphocytes.
Multiple myeloma (MM) is a cancer of plasma cells, characterized by profound suppression of host immune responses. Here we show that MM cell lines significantly suppress the proliferation, blasting, response to interleukin-2 (IL-2), and expression of CD25 by concanavalin A (Con A)-activated or allostimulated peripheral blood T lymphocytes. T cells arrest in the G1 stage of the cell cycle, and do not enter the IL-2 autocrine growth pathway. T cell inhibition was mediated by a soluble factor. MM cell lines did not produce IL-10 but did produce large amounts of transforming growth factor beta1 (TGF-beta1). T cells were assessed for their ability to respond to IL-2 when co-cultured with MM cells in the presence or absence of the TGF-beta inhibitor, TGF-beta latency-associated peptide (LAP). MM cells suppressed IL-2 responses but this inhibition was completely reversed by TGF-beta LAP. A CD25-, IL-2-dependent blast cell line was not inhibited by MM cells or rhTGF-beta, confirming the specificity of the inhibition mechanism for the IL-2 autocrine growth pathway. We conclude that MM cells suppress T cells in their entry into the autocrine IL-2/CD25 pathway and in response to IL-2, and that TGF-beta has a significant role to play.
Cook
G
G
Department of Medicine, University of Glasgow, Royal Infirmary, United Kingdom.
Campbell
J D
JD
Carr
C E
CE
Boyd
K S
KS
Franklin
I M
IM
D000276:Adjuvants, Immunologic / Q000037:antagonists & inhibitors* / Q000502:physiology; D017209:Apoptosis / Q000276:immunology; D002450:Cell Communication / Q000276:immunology; D002453:Cell Cycle / Q000276:immunology; D018920:Coculture Techniques; D003208:Concanavalin A / Q000037:antagonists & inhibitors; D006801:Humans; D007376:Interleukin-2 / Q000037:antagonists & inhibitors* / Q000502:physiology; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology*; D007959:Lymphocyte Culture Test, Mixed; D008934:Mitogens / Q000037:antagonists & inhibitors; D009101:Multiple Myeloma / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D010446:Peptide Fragments; D011498:Protein Precursors; D011506:Proteins / Q000494:pharmacology; D015375:Receptors, Interleukin-2 / Q000096:biosynthesis; D011994:Recombinant Proteins / Q000494:pharmacology; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000096:biosynthesis / Q000494:pharmacology*; D053773:Transforming Growth Factor beta1; D014407:Tumor Cells, Cultured
D000276:Adjuvants, Immunologic; D007376:Interleukin-2; D008934:Mitogens; D010446:Peptide Fragments; D011498:Protein Precursors; D011506:Proteins; D015375:Receptors, Interleukin-2; D011994:Recombinant Proteins; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D003208:Concanavalin A