Abstract
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-gamma)-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-gamma-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.
Highlights
Antigen-driven activation of naıve T cells during the course of an immune response to an infection results in massive expansion of antigen-specific T cells [9, 18]
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
We and others have recently shown that Bcl-2 family members play a significant role in the apoptotic demise of activated effector T cells during acute and chronic viral infections [12, 20, 27]
Summary
Antigen-driven activation of naıve T cells during the course of an immune response to an infection results in massive expansion of antigen-specific T cells [9, 18]. Mice inoculated with a low dose of L. major in one ear are protected from rechallenge in the second ear, despite the presence of a low-level chronic infection in the primary ear, a phenomenon known as “concomitant immunity” [16]. In this model, elimination of L. major either through removal of T regulatory cells by anti-CD25 depletion in vivo or via ablation of IL-10 in vivo results in loss of protective immunity against rechallenge with L. major [5, 16]. Natural model of L. major infection, parasite persistence is controlled by the presence of T regulatory cells and is linked to the maintenance of protective immunity against reinfection
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