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

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 Bimmediated 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 Bimmediated 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.

Bim controls IL-15 availability and limits engagement of multiple BH3-only proteins

“…Germline deletion of the pro-apoptotic Bcl-2 family member, Bim, enhances CD4 þ and CD8 þ T-cell responses to viral, bacterial and parasitic infection. [11][12][13][14] One report suggested a minor role for another Bcl-2 homology domain 3 (BH3)-only Bcl-2 family member, Puma, although the role of Puma on effector T-cell subsets was not examined. 15 Noxa has a marginal role in contraction of T-cell responses.…”

Mcl-1 antagonizes Bax/Bak to promote effector CD4+ and CD8+ T-cell responses

“…12,14 However, the molecular mechanism(s) by which Bim is normally antagonized to promote effector T-cell survival remains unclear.…”

Evaluation of s.c. route of immunization by homologous radio attenuated live vaccine in experimental murine model of visceral leishmaniasis

“…In case of s.c. route, the primary encounter DC is the main antigen presenting cell (APC) that activates the resting T-cells and immunization itself will generate its own set of T-reg cells. Thus it is better to select a route where T-reg cells will not be overrepresented (Reckling et al 2008) The skin contains the highest percentage of natural T-reg cells of the body and they can be expanded by the delivery of antigen under the immunogenic condition (Reckling et al 2008). Hence it is preferred to select a route for vaccination where the T-reg priming and activation will be minimum.…”