Control of B cell proliferation: Arrest of B cells in late G₁ underlies immunosuppression induced by plasma cell tumors

Immunosuppression in mice bearing plasma cell tumors (PC-mice) provides a model system for the study of negative B cell regulation. Our previous studies demonstrated that B cell proliferation is suppressed in these mice by a cascade of interactions involving macrophages and soluble factors. The present report pinpoints the G₁ phase of the cell cycle as the stage of B cell proliferation inhibited in PC-mice. Modulation of surface immunoglobulin (sIg) with anti-μ, an early membrane activation event, occurred normally on B cells from the spleens of PC-mice. However, examination of the size profile and the expression of sIgD and sIgM on B cells from the spleens of PC-mice showed an accumulation of large-sized, low intensity sIgD⁺ cells, suggesting a block in B cell activation in the late G₁ phase of the cell cycle. This was confirmed by experiments in vitro that demonstrated that although LPS-stimulated B cells from the spleens of PC-mice enlarged to a size characteristic of G₁ phase, most did not additionally enlarge into S phase even after 3 days of culture, nor did they incorporate significant amounts of [³H]thymidine. Additional confirmation of a block in late G₁ was obtained by using analysis of [³H]thymidine incorporation, cell size, and cell cycle after normal cells were cultured in supernatants from cloned PC lines containing the factor(s) that initiates the cascade of events leading to suppression of B cell proliferation. The relevance of these findings to PC-induced immunosuppression and to the regulation of normal B cell proliferation during the G₁ phase of the cell cycle is discussed.