Abstract
Aurora A is a serine/threonine kinase whose role in cell cycle progression and tumour generation has been widely studied. Recent work has revealed an unexpected function for Aurora A during CD4+ T cell activation and, also, in graft versus host disease development. However, it remains unknown whether Aurora A is involved in CD8+ T cell effector function and in cytotoxic T lymphocyte-mediated antiviral response. Here, we show that Aurora A chemical inhibition leads to an impairment of both the peptide-specific cytotoxicity and the degranulation activity of CD8+ T cells. This finding was similarly proven for both mice and human CD8+ CTL activity. As a result of Aurora A blockade, we detected a reduction in the expression induced by T cell activation of genes classically related to the effector function of cytotoxic T lymphocytes such as granzyme B or perforin1. Finally, we have found that Aurora A is necessary for CD8+ T cell-mediated antiviral response, in an in vivo model of vaccinia virus infection. Thus, we can conclude that Aurora A activity is, indeed, needed for the proper effector function of cytotoxic T lymphocytes and for their activity against viral threats.
Highlights
Aurora A, a serine/threonine kinase involved in cell cycle progression, has mainly been studied in the context of cell division and tumorigenesis[1,2,3]
We have assessed whether Aurora A plays a role in CD8+ T lymphocytes cytotoxic activity and their ability to respond against viruses
Target cells were previously pulsed with the H-2 Kb-restricted Ovalbumin peptide (257–264; ovalbumin peptide (OVAp)), or left unpulsed; stained with CFSE (1 and 0.1 μM, respectively) and mixed in a 1:1 ratio
Summary
CD8+ T cell-mediated cytotoxic response, OTI mouse T lymphoblasts were cocultured for 6 h with target cells (EL4 cell line) in the presence of Aurora A specific inhibitor (MLN8237) or vehicle (DMSO). MLN8237-treated infected mice that have not been adoptively transferred with OTI CD8+ T cells (grey squares), included as control, showed a decrease in viral titration compared to the vehicle-treated ones (black squares) (Fig. 3B) This suggests that Aurora A inhibition by MLN8237 might be interfering with viral replication per se or enhancing the innate immune clearance of the virus. Since CD8+ T cells transfer leads to a viral content still higher in the presence of MLN8237 than in vehicle treated mice, the reduction of the cytotoxic activity by Aurora A inhibition would be even stronger than the one detected These results show that Aurora A acts as a key molecule in the effector function of cytotoxic T lymphocytes, both in mice and human. Considering the involvement of autoreactive CD8+ T cells in the generation of tissue damage on some autoimmune disorders, such as diabetes[18], the results from this work unveil new applications for Aurora A inhibitors, such as the blockade of effector CTLs in order to prevent tissue damage and, improve the outcome of these disorders
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