Role of Bim in Regulating CD8<sup>+</sup>T-Cell Responses during Chronic Viral Infection

Grayson, Jason M.; Weant, Ashley E.; Holbrook, Beth C.; Hildeman, David A.

doi:10.1128/jvi.00855-06

Cited by 62 publications

(64 citation statements)

References 50 publications

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“…However, this study has not investigated the roles of different APC types. Similarly, bim was found to delete immunodominant CTL responses in a murine model of chronic LCMV responses [41], explaining earlier reports of high dose antigenic deletion of LCMV-specific CTL [42].…”

Section: Discussionsupporting

confidence: 67%

Parenchymal cells critically curtail cytotoxic T‐cell responses by inducing Bim‐mediated apoptosis

et al. 2010

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To develop cytolytic effector functions, CD8 1 T lymphocytes need to recognize specific Ag/ MHC class I complexes in the context of costimuli on Ag-presenting DC. Thereafter they differentiate into effector and memory CTL able to confer protection against pathogen infection. Using transgenic mice with DC-selective MHC class I expression and DC-specific versus ubiquitous vaccination regimen, we found that DC are sufficient to prime CTL responses. However, Ag recognition on parenchymal non-professional APC negatively affected CD8 1 T-cell responses in mice by inducing expression of the pro-apoptotic bcl2-family member bim in CTL. This unexpected induction of apoptosis in the early phase of effector CTL accumulation lead to suboptimal clonal burst size and diminished long-term memory. Thus, our data demonstrate that effector CTL differentiation and apoptosis are regulated independently. Moreover, Ag distribution on cells other than DC critically reduces CTL responses.

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Section: Discussionsupporting

confidence: 67%

Parenchymal cells critically curtail cytotoxic T‐cell responses by inducing Bim‐mediated apoptosis

et al. 2010

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“…Previous work by us and others showed that Bim was required for apoptotic contraction of superantigen-reactive and virus-specific T cells in vivo (12,14,20,27). We showed that following infection with lymphocytic choriomeningitis virus (LCMV), the absence of apoptotic contraction in Bim Ϫ/Ϫ mice resulted in significantly increased numbers of memory pheno- FIG.…”

Section: Discussionmentioning

confidence: 78%

“…This decision between death and survival is crucial for avoiding autoimmunity and for promoting the development of immunological memory and protective immunity. 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). However, it remains unclear whether the failure to eliminate effector T cells can result in functionally increased protective immunity in vivo.…”

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confidence: 99%

“…We and others have recently shown that the proapoptotic Bcl-2 family member Bim plays a critical role in the apoptotic demise of activated T cells in vivo (12,14,20,27). The proapoptotic activity of Bim is kept in check by the antiapoptotic molecule Bcl-2 (7,28); just prior to the apoptotic demise of T cells in vivo, Bcl-2 levels are significantly decreased, and this allows Bim to trigger apoptosis (13,14,17).…”

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confidence: 99%

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

et al. 2008

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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.

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“…Apoptosis of CD8 + T cells is controlled by the intrinsic (or mitochondrial) pathway, which is mediated by activation of the proapoptotic BH3-only proteins (e.g., Bcl-2-interacting mediator of death [Bim]), and the extrinsic pathway, which is mediated by ligation of death receptors (e.g., Fas or TNFR) (3,9). The Bimmediated intrinsic pathway controls both T cell contraction in acute infection and the persistence of Ag-specific CD8 + T cells in chronic infection (3,(10)(11)(12)(13)(14)(15). In acute infections, Fas/Fas ligand (FasL)-triggered cell death is dispensable for CD8 + T cell contraction (13,16); however, it could compensate for the loss of Bim in another infection model (14), and both Bim and Fas were shown to cooperate in controlling the cell death of Ag-stimulated CD8 + T cells in chronic infection (12,(17)(18)(19).…”

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confidence: 99%

Id3 Controls Cell Death of 2B4+ Virus-Specific CD8+ T Cells in Chronic Viral Infection

Menner

Rauch

Aichele

et al. 2015

The Journal of Immunology

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Sustained Ag persistence in chronic infection results in a deregulated CD8+ T cell response that is characterized by T cell exhaustion and cell death of Ag-specific CD8+ T cells. Yet, the underlying transcriptional mechanisms regulating CD8+ T cell exhaustion and cell death are poorly defined. Using the experimental mouse model of lymphocytic choriomeningitis virus infection, we demonstrate that the transcriptional regulator Id3 controls cell death of virus-specific CD8+ T cells in chronic infection. By comparing acute and chronic infection, we showed that Id3− virus-specific CD8+ T cells were less abundant, whereas the absolute numbers of Id3+ virus-specific CD8+ T cells were equal in chronic and acute infection. Phenotypically, Id3− and Id3+ cells most prominently differed with regard to expression of the surface receptor 2B4; although Id3− cells were 2B4+, almost all Id3+ cells lacked expression of 2B4. Lineage-tracing experiments showed that cells initially expressing Id3 differentiated into Id3−2B4+ cells; in turn, these cells were terminally differentiated and highly susceptible to cell death under conditions of persisting Ag. Enforced Id3 expression specifically increased the persistence of 2B4+ virus-specific CD8+ T cells by decreasing susceptibility to Fas/Fas ligand–mediated cell death. Thus, our findings reveal that the transcriptional regulator Id3 promotes the survival of virus-specific CD8+ T cells in chronic infection and suggest that targeting Id3 might be beneficial for preventing cell death of CD8+ T cells in chronic infection or for promoting cell death of uncontrolled, hyperactive CD8+ T cells to prevent immunopathology.

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Role of Bim in Regulating CD8⁺T-Cell Responses during Chronic Viral Infection

Cited by 62 publications

References 50 publications

Parenchymal cells critically curtail cytotoxic T‐cell responses by inducing Bim‐mediated apoptosis

Parenchymal cells critically curtail cytotoxic T‐cell responses by inducing Bim‐mediated apoptosis

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

Id3 Controls Cell Death of 2B4+ Virus-Specific CD8+ T Cells in Chronic Viral Infection

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Role of Bim in Regulating CD8+T-Cell Responses during Chronic Viral Infection

Cited by 62 publications

References 50 publications

Parenchymal cells critically curtail cytotoxic T‐cell responses by inducing Bim‐mediated apoptosis

Parenchymal cells critically curtail cytotoxic T‐cell responses by inducing Bim‐mediated apoptosis

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

Id3 Controls Cell Death of 2B4+ Virus-Specific CD8+ T Cells in Chronic Viral Infection

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Role of Bim in Regulating CD8⁺T-Cell Responses during Chronic Viral Infection