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Follicular Dendritic Cells Protect Malignant B Cells from Apoptosis Induced by Anti-Fas and Antineoplastic Agents¹

Ying X. Schwarz^*, Ming-yan Yang^*, Dahui Qin^*, Jiuhua Wu^*, W. David Jarvis, Steven Grant, Gregory F. Burton^*, Andras K. Szakal and John G. Tew^2,*

Departments of ^* Microbiology and Immunology, Medicine, and Anatomy, Division of Immunobiology, Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, VA 23298

The observation that follicular dendritic cells (FDC) reduce apoptosis in B cells prompted the hypothesis that FDC might enhance tumor cell survival by protecting malignant B cells from apoptotic death. To test this notion, apoptosis was induced in B cell lymphomas by anti-Fas or various antineoplastic agents in the presence and absence of FDC. Apoptosis was detected and quantified by TUNEL analysis. Induction of apoptosis with anti-Fas, etoposide, cyclophosphamide, and busulfan was markedly antagonized by FDC at FDC to B cell ratios of 1:16. For example, treatment with 10 ng/ml anti-Fas caused 60–90% of A20 cells to undergo apoptosis in 6 h, whereas addition of FDC reduced apoptosis to background levels (3–15%). Similarly, treatment with busulfan induced apoptosis in 55–80% of A20 cells, whereas addition of FDC reduced B cell death to 15%; moreover, depletion of FDC abrogated the protective actions. In contrast, the apoptosis-inducing effect of Adriamycin was not reversed by FDC. The ability to block apoptosis induced by anti-Fas or busulfan was not limited to A20 but was observed in four other malignant pre-B cell or B cell lines. The mechanism by which FDC spare malignant B cells from apoptosis did not involve alterations in levels of Bcl-2, Bcl-X_L, or Bax. Collectively, these data raise the possibility that FDC may enhance tumor cell survival by protecting malignant B cells against apoptosis induced by anti-Fas and some but not all chemotherapeutic agents.