CD23 antigen regulation and signaling in chronic lymphocytic leukemia.

B lymphocytes from patients with chronic lymphocytic leukemia (B-CLLs), strongly express the CD23 antigen, a surface marker with significant prognostic importance in this disease. Because we previously reported that IL4 shows a poor capac- ity for CD23 expression on B-CLLs, we first examined the possible mechanisms underlying CD23 overexpression on B-CLLs and found that mitogen-activated CLL T cells release soluble factors that are capable, in synergy with IL4, of strongly inducing CD23. Using neutralizing Abs, we noticed that the T-cell-derived enhancing activity is entirely ascribed to the combined effects of IFN'y (potent inhibitor of CD23 on normal B cells), TNFa (which has no effect on normal B cells), and IL-2 (which has a slight enhancing effect on both CLL and normal B cells). Furthermore, recombinant IFN'y as well as IFNa, TNFa, and IL-2 (but not IL-3, IL-5, IL-6, IL-7, and lymphotoxin) significantly enhance CD23 protein and mRNA expression on B-CLLs, in the presence or absence ofIL4. Inasmuch as optimal CD23 expression absolutely requires the com- bination of IFN'y, IL-2, TNFa (the production of which is in- creased in CLL disease), and IL4, it was relevant to show that IL4 mRNA is indeed expressed in fresh T-CLL cells. We next examined the possible role of CD23 in the regulation of B-CLL proliferation. Signaling through CD23 via ligation of the anti- gen by F(ab)2 anti-CD23 MAb but not Fab fragments inhibits the cytokine-induced B-CLL DNA synthesis. It is concluded that the CD23 gene is abnormally regulated in B-CLL disease and that cross-linking of CD23 molecule delivers a negative growth signal to the leukemic B cells. (J. Clin. Invest. 1992 . 89:1312-1321.) Key words: interferon-a * interferon-y * inter- leukin 4-CD23 antigen regulation * tumor necrosis factor-a Methods Reagents. Human recombinant IL-2 was purchased from Genzyme Corp. (Boston, MA). Recombinant IFNy and natural human IFNy were purchased from Alpha-Therapeutic Corp. (Los Angeles, CA) and Cellular Products (Buffalo, NY), respectively. Human recombinant IL- 1. Abbreviations used in this paper: CLL, chronic lymphocytic leuke- mia; B-CLLs and T-CLLs, purified B or T cells, respectively, isolated from CLL patients; GM-CSF, granulocyte/macrophage colony-stimu- lating factor; MFI, mean fluorescence intensity; PCR, polymerase chain reaction; PDGF, platelet-derived growth factor, sCD23/IgE-BF, IgE-binding factor or soluble CD23; TGFB2, transforming growth fac- tor-,B2; TNFa