A major problem of infections with facultative intracellular bacteria is their chronic course. We comprehensively evaluated the host response in murine brucellosis to study mechanisms contributing to bacterial persistence in the presence of an established immune response. Evidence is presented that the decrease in eradication kinetics, reproducibly occurring 18 d after infection of mice with Brucella abortus S19, is related to a state of downregulation of defense mechanisms. This is not due to a Th1 to Th2 switch or prostaglandin-mediated suppression by macrophages but is most probably caused by a severe disruption of spleen morphology at the height of Brucella-induced delayed type hypersensitivity. This results in a profound depletion of both CD4(+) and CD8(+) T cells in periarteriolar lymphatic sheaths, a consecutive deleterious shift in the relation of permissive macrophages and protective lymphocytes and an impaired capacity of splenocytes to produce IFN-gamma in response to soluble Brucella antigen.