Viral Immunity: Role for Bim in termination of immune responses

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The BH3-only pro-apoptotic BCL-2-family member Bim is a crucial inducer of programmed cell death in the lymphoid lineage.

The BH3-only pro-apoptotic BCL-2-family member Bim is required for the death of activated T cells during the resolution of antiviral T-cell responses in vivo, according to the latest findings from an Australian group now published in the Proceedings of the National Academy of Sciences.

Viral infection leads to rapid antigen-driven clonal expansion of T cells that acquire effector functions and eliminate infected cells. Clearance of antigen is associated with a downregulation of the immune response and apoptosis of most antigen-specific T cells. Apoptosis can be mediated by signalling downstream of death receptors, members of the tumor-necrosis factor receptor (TNFR) family such as FAS (CD95) or TNFR1, or by pathways involving pro- and anti-apoptotic members of the BCL-2 family. Here, Pellegrini and colleagues investigated the involvement of Bim and CD95 in T-cell responses to infection with herpes simplex virus (HSV).

The kinetics of CD8⁺ T-cell responses to HSV in the lymph nodes of wild-type, Bim^-/- and CD95-deficient lpr mice were similar, with infection leading to a rapid increase in the number of HSV-specific CD8⁺ T cells, which peaked at 7 days after infection. By 14 days, most of these T cells had disappeared from the lymph nodes. However, when the authors looked in the spleens of these mice, they saw an accumulation of HSV-specific CD8⁺ T cells in the Bim-deficient mice that did not occur in the wild-type or lpr mice.

Why does loss of Bim function lead to increased numbers of virus-specific T cells in the spleens of Bim^-/- mice? Further experiments showed that this accumulation did not result from prolonged activation or excessive proliferation of HSV-specific CD8⁺ T cells in these mice, or from differences in the trafficking of T cells. Neither was persistent viral infection responsible, as the kinetics of viral clearance were similar in Bim^-/- mice, lpr mice and wild-type mice. HSV-specific CD8⁺ T cells were shown to build up in the spleens of Bim^-/- mice, but not in wild-type or lpr mice, due to these cells being resistant to apoptosis induced by cytokine withdrawal.

The authors conclude that neither CD95 nor Bim are required for viral clearance, but that Bim (and not CD95) is required for the apoptosis of virus-specific CD8⁺ T cells after clearance of HSV infection. Previous studies have shown that Bim is essential for the deletion of autoreactive B and T cells. Collectively, these results indicate that Bim is a crucial inducer of programmed cell death in the lymphoid lineage.

Jenny Buckland

References

Pellegrini, M. et al. Shutdown of an acute T cell immune response to viral infection is mediated by the proapoptotic Bcl-2 homology 3-only protein Bim. Proc. Natl Acad. Sci. USA 100, 14175–14180 (2003) | Article | PubMed |
Bouillet, P et al. BH3-only Bcl-2 family member Bim is required for apoptosis of autoreactive thymocytes. Nature 415, 922–926 (2002) | Article | PubMed |
Bouillet, P. et al. Proapoptotic Bcl-2 relative Bim required for certain apoptotic responses, leukocyte homeostasis, and to preclude autoimmunity. Science 286, 1735–1738 (1999) | Article | PubMed |
Enders, A. et al. Loss of the pro-apoptotic BH3-only Bcl-2 family member Bim inhibits BCR stimulation-induced apoptosis and deletion of autoreactive B cells. J. Exp. Med. 198, 1119–1126 (2003) | Article | PubMed |