The aly is a unique spontaneous autosomal recessive mutation in mice that causes a systemic defect of lymph nodes and Peyer's patches. We investigated host resistance against Listeria monocytogenes infection in the mutant. The 50% lethal dose of L. monocytogenes in aly/aly mice was 10-fold higher than their heterozygotes, termed aly/+mice, or their wild-type C57BL/6 mice. The bacterial growth in the spleens and livers of aly/aly mice was more efficient early in infection, and their listericidal activity of peritoneal macrophages was higher than those of aly/+mice. In contrast, the complete elimination of bacteria from the spleens and livers of infected mice in the late stage of infection, in which a T-cell-dependent mechanism is required, was delayed in the aly/aly mice. Moreover, an acquired resistance against secondary infection with L. monocytogenes was markedly diminished in the aly/aly mice. The production of endogenous interferon-gamma (IFN-gamma) and tumor necrosis factor-alpha (TNF-alpha), which are critical in antilisterial resistance, was reduced in the aly/aly mice during the infection. The production of IFN-gamma, and interleukin-4 was also diminished in the spleen cell cultures of aly/aly mice when stimulated with heat-killed L. monocytogenes or the T-cell receptors were directly stimulated with anti-CD3-epsilon monoclonal antibody. These results suggest that acquired immunity against L. monocytogenes infection is attenuated in aly/aly mice, and that the insufficient production of IFN-gamma and TNF-alpha might be involved in the immunodeficiency.