Infection of mice with Listeria monocytogenes has led to a puzzling observation: mice deficient in lymphocytes are more resistant during the early innate immune response. This is counterintuitive, because mice deficient in the adaptive immune response are unable to clear the infection and eventually die. This work will highlight some of our recent work on Listeria induced apoptosis and its immunological consequences. We show that Listeria produces a toxin, listeriolysin O (LLO), which causes apoptosis of lymphocytes in vitro and in vivo. Early during the infection, type I interferon sensitizes lymphocytes to die by LLO-induced apoptosis. The cell death peaks during the first two days of the infection, leading to the production of IL-10 and downregulation of anti-microbial activity in the spleen. The induction of apoptosis by Listeria creates an infective niche in the peri-arteriolar lymphoid sheaths of the spleen which allows the bacteria to grow exponentially.