Anti-proliferative agents that target lymphoid cells are common immunosuppressive agents used in the treatment of diverse autoimmune, graft versus host and inflammatory diseases. Mycophenolate mofetil (MMF) is an anti-proliferative agent that targets lymphoid dependence on inosine monophosphate dehydrogenase for the de novo purine synthesis of deoxyguanosine triphosphate (dGTP) for DNA replication. Here we show that MMF has a distinct and specific in vivo effect on macrophages, in the absence of lymphoid cells. This results in increased macrophage cell death that is dependent on the depletion of cellular GTP, independent of DNA synthesis. Furthermore, the macrophage specific effect of MMF treatment causes an increase in susceptibility to the opportunistic fungal infectionCryptococcus neoformans by reducing phagocytosis and increasing the release of intracellular pathogens via macrophage lysis. Our study demonstrates the need for a better mechanistic understanding of immunosuppressive treatments used in clinical practice and of the specific infection risks associated with certain treatment regimens.

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