Growth control of activated, synchronized murine B cells by the C3d fragment of human complement

Abstract

Three restriction points control the cell cycle of activated B lymphocytes¹. The first occurs directly after mitosis and is controlled by the occupancy of surface-bound immunoglobulin. The second is observed ∼ 4 h after mitosis in the G₁ phase of the cycle, that is, before DNA replication, and is controlled by growth factors that are produced by macrophages² which we have previously classified as α-type factors^3,4. The third restriction point occurs in the G₂ phase, 2–4 h before mitosis, and is controlled by β-type growth factors probably produced by helper T lymphocytes⁵. The third component of complement, C3, has long been implicated in the control of B-cell responses^6–12. C3 is secreted by monocytes and macrophages^13,14. We have found recently that crosslinked, but not soluble, human C3 stimulates activated, but not resting, murine B cells to thymidine uptake¹⁵. Here we investigate the role of C3b and C3d in the progression of the cell cycle of activated, synchronized murine B cells. We find that crosslinked C3d replaces the action of α-factors within the cell cycle of these cells and allows entry into S phase. In contrast, soluble C3d inhibits the action of α-factors. This implies that a C3d-specific receptor, probably the murine analogue to the human complement receptor CR2 (refs 16, 17), is a growth factor receptor on activated B cells that will give the cell a growth-positive signal when it is crosslinked, while occupancy by the soluble form of C3d will result in inhibition of the action of α-factors or of crosslinked C3b or C3d. A stretch of weak homology between the cDNA sequence of murine C3d and those of murine growth factors indicates that an insulin-like growth factor could be the active principle of C3d that controls the cell cycle of activated B cells.