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Infect. Immun. doi:10.1128/IAI.01093-06
Copyright (c) 2007, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

PRO-APOPTOTIC BCL-2 FAMILY MEMBER BIM PROMOTES PERSISTENT INFECTION AND LIMITS PROTECTIVE IMMUNITY

Divisions of Molecular Immunology, and Immunobiology, Cincinnati Children's Hospital Medical Center and the University of Cincinnati, Cincinnati, Ohio 45229, USA

^* To whom correspondence should be addressed. Email: ybelkaid{at}niaid.nih.gov. David.Hildeman{at}cchmc.org.

	Abstract

Following the peak of the T cell response, most of the activated, effector T cells die by apoptosis driven by the pro-apoptotic 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 interferon--producing effector T cells and IL-10 producing, CD4+ CD25+ regulatory T cells (Tregs). To further understand the role of Bim-mediated apoptosis on persistant infection and protective immunity, we infected Bim^-/- mice with L. major. We found that initial parasite growth and lesion development were similar between 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 from challenge with L. major. Increased resistance to challenge in Bim^-/- mice was associated with significantly increased L. major-specific IFN--producing CD4+ T cells and 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 re-infection.