Ligation of CD38 suppresses human B lymphopoiesis.

Abstract

I@Sllnlnlagy CD38 is a transmembrane glycoprotein expressed in many cell types, including lymphoid progenitors and activated lymphocytes. High levels of CD38 expression on immature lymphoid cells suggest its role in the regulation of cell growth and differentiation, but there is no evidence demonstrating a functional activity of CD38 on these cells. We used stroma-supported cultures of B cell progenitors and anti-CD38 monodonal antibodies (T16 and IB4) to study CD38 function. In cultures of normal bone marrow CD19 + cells (n = 5), addition of anti-CD38 markedly reduced the number of cells recovered after 7 d. Cell loss was greatest among CD19 § slg-B cell progenitors (mean cell recovery +_ SD = 7.2 _ 11.7% of recovery in control cultures) and extended to CD19~CD34 + B cells (the most immature subset; 7.6 • 2.2%). In contrast, CD38 ligation did not substantially affect cell numbers in cultures of normal peripheral blood or tonsiUar B cells. In stroma-supported cultures of 22 B-lineage acute lymphoblastic leukemia cases, anti-CD38 suppressed recovery of CD19 + slg-leukemic calls. CD38 ligation also suppressed the growth of immature lymphoid cell lines cultured on stroma and, in some cases, in the presence of stroma-derived cytokines (interleukin [IL] 7, II-3, and/or stem cell factor), but did not inhibit growth in stroma-or cytokine-free cultures. DNA content and DNA fragmentation studies showed that CD38 ligation of stroma-supported cells resulted in both inhibition of DNA synthesis and induction of apoptosis. It is known that CD38 catalyzes nicotinamide adenine dinudeotide (NAD+) hydrolysis into cyclic ADP-ribose (cADPR) and ADPR. However, no changes in NAD+ hydrolysis or cADPR and ADPR production after CD38 ligation were found by high-performance liquid chromatography; addition of NAD+, ADPIL, or cADPK to cultures of lymphoid progenitors did not offset the inhibitory effects of anti-CD38. Thus, anti-CD38 does not suppress B lymphopoiesis by altering the enzymatic function of the molecule. In conclusion, these data show that CD38 ligation inhibits the growth of immature B lymphoid cells in the bone marrow microenvironment, and suggest that CD38 interaction with a putative ligand represents a novel regulatory mechanism of B lymphopoiesis.

The metamorphosis of a molecule: from soluble enzyme to the leukocyte receptor CD38

“…The most severely affected cells are surface immunoglobulin negative (sIg Ϫ ). The effect does not occur with circulating or tonsillar B cells [9]. Like CD38, the CD157 receptor seems to play an especially important role in B lymphocyte development and function [6,40].…”

“…Splenic B cells proliferate in response to IB4 mAb [39]. Addition of anti-CD38 mAbs (either IB4 or T16) to normal bone marrow B cells (Ͼ90% CD38 ϩ ) co-cultured on stromal layers (mostly CD38 Ϫ but CD157 ϩ ) drastically reduces the number of cells recovered after a 7-day culture period [9]. The most severely affected cells are surface immunoglobulin negative (sIg Ϫ ).…”

“…CD38 also marks T lymphocyte ontogenesis: Ͼ80% of medullary thymocytes are CD38 ϩ , peripheral blood T cells are mostly CD38 Ϫ , whereas activated T cells are strongly CD38 ϩ [8]. In B lymphocyte ontogenesis, Ͼ90% BM B cell progenitors are CD38 ϩ [9], circulating B cells are CD38 Ϫ , whereas plasma cells are strong expressors [8]. CD38 is easily detected on NK cells and, among myeloid cells, most circulating monocytes are CD38 ϩ , whereas neutrophils [10] and endothelial cells (EC) [11] are negative.…”

“…As we leave the immune function of CD38 to explore its life as an enzyme, it should be pointed out that in the few cases tested so far, the catalytic activities of CD38 do not seem to be involved in its immunological performances [9,31].…”

Association of phosphatidylinositol 3‐kinase with the photo‐oncogene product Cbl upon CD38 ligation by a specific monoclonal antibody in THP‐1 cells

“…immune system, as inferred from the observation that CD38 ligation by agonistic mAbs elicits a variety of cell functions, including cell proliferation, lymphopoiesis, apoptosis, adhesion and cytokine production [2,8,9]. CD38 ligation by mAbs is believed to mimic some of the events triggered by the binding with a natural ligand.…”