Ej. Schattner et al., CD40 LIGATION INDUCES APO-1 FAS EXPRESSION ON HUMAN B-LYMPHOCYTES ANDFACILITATES APOPTOSIS THROUGH THE APO-1/FAS PATHWAY/, The Journal of experimental medicine, 182(5), 1995, pp. 1557-1565
The Apo-1/Fas antigen (CD95) mediates programmed cell death of lymphoc
ytes when bound by Fas ligand or anti-Apo-1/Fas antibody. In contrast,
the CD40 antigen provides a potent activation and survival signal to
B lymphocytes when it is engaged by its T cell ligand (CD40L, gp39) or
cross-linked by anti-CD40 antibody. In this study, we use human tonsi
llar B cells and the Ramos Burkitt's lymphoma B cell line, which serve
s as a model for human germinal center B lymphocytes, to study the eff
ecters of Apo-1/Fas expression and apoptosis of human B cells. We foun
d that Apo-1/Fas expression was upregulated on both malignant and norm
al human B lymphocytes after CD40 ligation induced by (a) cognate T he
lper-B cell interaction mediated by microbial superantigen (SAg); (b)
contact-dependent interaction with CD40L(+), but not CD40L(-) Jurkat m
utant T cell clones; and (c) monoclonal anti-CD40, but not any of a pa
nel of control antibodies. Enhanced B cell Fas/Apo-1 expression is fun
ctionally significant. Coculture of Ramos Burkitt's lymphoma line cell
s with irradiated SAg-reactive CD4(+) T cells with SAg or CD40L(+) Jur
kat T cells results in B cell apoptosis, evidenced by reduced cell via
bility and DNA laddering. This process is augmented by the addition of
anti-Apo-1/Fas monoclonal antibody, consistent with an acquired susce
ptibility to Apo-1/Fas-mediated apoptosis. These data support an immun
oregulatory pathway in which seemingly contradictory signals involving
the B cell proliferation/survival antigen CD40, as well as the Apo-1/
Fas molecule, which mediates programmed cell death of lymphocytes, are
linked in the process of human B cell activation.