Alternatively activated macrophages induced by nematode infection inhibit proliferation via cell-to-cell contact

The cytokine microenvironment is thought to play an important role in the g eneration of immunoregulatory cells. Nematode infections are commonly assoc iated with Th2 cytokines and hyporesponsive T cells. Here we show that IL-4 -dependent macrophages recruited in vivo by the nematode parasite Brugia ma layi actively suppress the proliferation of lymphocytes on co-culture in vi tro. These alternatively activated macrophages block proliferation by cell- to-cell contact, implicating a receptor-mediated mechanism. Further, the pr oliferative block is reversible and is not a result of apoptosis. Suppresse d cells accumulate in the G1 and G2/M phase of the cell cycle. Interestingl y, the G1 and G2/M block correlates with increased levels of Ki-67 protein, suggesting a mechanism that affects degradation of cell cycle proteins. We also show that, in addition to lymphocyte cell lines of murine origin, the se suppressive cells can inhibit proliferation of a wide range of transform ed human carcinoma lines. Our data reveal a novel mechanism of proliferativ e suppression induced by a parasitic nematode that acts via IL-4-dependent macrophages. These macrophages may function as important immune regulatory cells in both infectious and noninfectious disease contexts.