Immune responses are efficient because the rare naïve antigen-specific cells proliferate extensively after antigen stimulation. This property raises an important paradox: how CD8 T cells may survive the DNA lesions necessarily induced during their extensive division without undergoing transformation. In secondary responses in the absence of CD4 help, cells with DNA damages are ensured to die. In the presence of CD4 help DDRs become very efficient, justifying the major amplitude of these secondary responses. These results highlight the fundamental role of DDRs in CD8 immune responses.
PLoS One. 2015;10(10):e0140849.
Galgano A1, Barinov A1, Vasseur F1, de Villartay JP2, Rocha B1.[expand title=”Show Affiliations”]
- INSERM, U1020, CNRS, UMR 8253, Medical Faculty Paris Descartes, Université Paris Descartes Sorbonne Paris Cité, Paris, France.
- INSERM, UMR 1163, Institut Imagine, Hôpital Necker-Enfants Malades, Paris, France. [/expand]
Immune responses are efficient because the rare antigen-specific naïve cells are able to proliferate extensively and accumulate upon antigen stimulation. Moreover, differentiation into memory cells actually increases T cell accumulation, indicating improved productive division in secondary immune responses. These properties raise an important paradox: how T cells may survive the DNA lesions necessarily induced during their extensive division without undergoing transformation. We here present the first data addressing the DNA damage responses (DDRs) of CD8 T cells in vivo during exponential expansion in primary and secondary responses in mice. We show that during exponential division CD8 T cells engage unique DDRs, which are not present in other exponentially dividing cells, in T lymphocytes after UV or X irradiation or in non-metastatic tumor cells. While in other cell types a single DDR pathway is affected, all DDR pathways and cell cycle checkpoints are affected in dividing CD8 T cells. All DDR pathways collapse in secondary responses in the absence of CD4 help. CD8 T cells are driven to compulsive suicidal divisions preventing the propagation of DNA lesions. In contrast, in the presence of CD4 help all the DDR pathways are up regulated, resembling those present in metastatic tumors. However, this up regulation is present only during the expansion phase; i.e., their dependence on antigen stimulation prevents CD8 transformation. These results explain how CD8 T cells maintain genome integrity in spite of their extensive division, and highlight the fundamental role of DDRs in the efficiency of CD8 immune responses.Go To PLoS One