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Proapoptotic Bcl-2 Family Member Bim Promotes Persistent Infection and Limits Protective Immunity

Divisions of Molecular Immunology,¹ Immunobiology, Cincinnati Children's Hospital Medical Center and University of Cincinnati, Cincinnati, Ohio 45229,² Laboratory of Parasitic Diseases, National Institutes of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20852³

Received 12 July 2006/ Returned for modification 14 September 2006/ Accepted 5 December 2007

Following the peak of the T-cell response, most of the activated effector T cells die by apoptosis driven by the proapoptotic Bcl-2 family member Bim (Bcl-2-interacting mediator of death). Whether the absence of Bim-mediated T-cell apoptosis can affect protective immunity remains unclear. Here, we used a mouse model of Leishmania major infection, in which parasite persistence and protective immunity are controlled by an equilibrium reached between parasite-specific gamma interferon (IFN-)-producing effector T cells and interleukin-10 (IL-10)-producing CD4⁺ CD25⁺ T regulatory cells. To further understand the role of Bim-mediated apoptosis in persistent infection and protective immunity, we infected Bim^–/– mice with L. major. We found that the initial parasite growth and lesion development were similar in Bim^–/– and wild-type mice after primary L. major infection. However, at later times after infection, Bim^–/– mice had significantly increased L. major-specific CD4⁺ T-cell responses and were resistant to persistent infection. Interestingly, despite their resistance to primary L. major infection, Bim^–/– mice displayed significantly enhanced protection against challenge with L. major. Increased resistance to challenge in Bim^–/– mice was associated with a significant increase in the number of L. major-specific IFN--producing CD4⁺ T cells and a lack of IL-10 production at the challenge site. Taken together, these data suggest that Bim limits protective immunity and that the absence of Bim allows the host to bypass antigen persistence for maintenance of immunity against reinfection.

Published ahead of print on 17 December 2007.

Editor: J. L. Flynn