CD77: an antigen of germinal center B cells entering apoptosis

Abstract

We have previously reported that a neutral glycolipid (globotriosylceramide; Gb3) was specifically expressed on Burkitt's lymphoma cells and on a subset of germinal center tonsillar B lymphocytes. Recently the Gb3 molecule was recognized as a new B cell differentiation antigen and now defines the CD77 cluster. Here we report an extensive phenotypic and functional characterization of the tonsillar CD77+ B lymphocytes. These cells have a low buoyant density and are thus purified using a Percoll gradient. They express various B cell antigens such as CD19, CD20, CD21, CD22 and CD40, as well as the adhesion molecules LFA-1, LFA-3 and CD44. They are positive for surface IgM and negative for surface IgD. Although these results suggest a phenotype of activated B cells, the CD77+ cells are negative for the classical activation antigens: CD23 (the low-affinity Fc receptor for IgE), CD25 [the interleukin (IL) 2 receptor alpha chain] and CD71 (the transferrin receptor). Proliferation and protein synthesis of CD77+ cells was measured after stimulation with a range of mitogens and IL. None of the agents tested are able to induce proliferation and protein synthesis with the exception of a combination of recombinant IL 4 plus anti-CD40 antibody. When examined by electron microscopy, CD77+ B lymphocytes present a morphology similar to that of cells undergoing programmed cell death, also called apoptosis (i.e. chromatin condensation, nuclear fragmentation, membrane blebbing). As shown by direct examination of DNA, these CD77+ cells are indeed in the process of apoptosis. Treatment of the CD77+ cells by recombinant IL 4 and anti-CD40 antibody prevents apoptosis. All these results suggest that the CD77 molecule defines a B lymphocyte maturation pathway, specific for germinal center, where the cells undergo programmed cell death.

CD40 ligand, Bcl-2, and Bcl-xL spare group I Burkitt lymphoma cells from CD77-directed killing via Verotoxin-1 B chain but fail to protect against the holotoxin

“…54 For group I BL cells, CD77 was found not to be requisite for the expression of an apoptotic phenotype per se. This possibility had been raised previously in regard to both BL and their normal GC B cell equivalents: 9,46 indeed, a mechanistic basis for this could be envisaged through a potential pro-apoptotic activity being generated from the intracellular ceramide moiety of CD77. Nevertheless, while the CD77 neg fraction of the L3055 line was clearly refractory to killing via both VT-1 B chain and holotoxin they remained fully susceptible to apoptosis induced by cross-linking their sIgM.…”

“…9,46 We assessed here whether the presence of CD77 on BL lines was requisite to their ability to undergo activation-induced PCD while attempting to confirm its necessity for VT-1-mediated killing. This was facilitated by the observation that the L3055 group I BL line maintained in early passage comprised a dual population of CD77 pos and CD77 neg cells at an approximate 2 : 1 ratio (Figure 1a).…”

A crucial role of plasma membrane-associated sialidase in the survival of human cancer cells

“…The former change was consistent with those observed previously in colon cancer, possibly owing to enhanced hydrolysis of GM3, and the latter change might be at least caused by activation of Gb3 synthase, as shown in Figure 6b. Interestingly, Gb3 has been characterized as the CD77 differentiation antigen inducing apoptosis (Mangeney et al, 1991). In addition to the glycolipid products, NEU3 might exert an influence on the signaling by interacting with some related molecules including EGFR, as shown in Figure 5c.…”

Molecular Cloning of Globotriaosylceramide/CD77 Synthase, a Glycosyltransferase That Initiates the Synthesis of Globo Series Glycosphingolipids

“…The observed rapid death of CD77 ϩ germinal center B cells in vitro suggests that endogenous ligand molecules interact with Gb3/CD77 to bring about the physiologic selection of immature B cells (12,35). Furthermore, the capability of the B subunit of VT to induce apoptosis of Gb3/CD77 ϩ cells (18) strongly encourages the investigation of Gb3/CD77-associating cytoplasmic molecules (34).…”

“…Among normal leukocytes, it is only expressed on a subset of tonsillar B cells in the germinal centers (10). Interestingly, germinal center B lymphocytes expressing Gb3/CD77 undergo rapid and spontaneous apoptosis when isolated and cultured in vitro (12). Furthermore, Burkitt's lymphoma cells with Gb3/CD77 antigen were also easily induced to enter apoptosis upon culture at low serum concentration or cross-linking by anti-immunoglobulin M antibodies (13).…”