Background: Activation of both CD4+T and CD8+T cells is triggered by the engagement of the T cell antigen receptor (TCR) with MHC/peptide complexes on antigen-presenting cells. This process also requires other molecular interactions, which transmit co-stimulatory signals to these T cells. To ensure an effective immune response, distinct T cell subsets may additionally employ unique mechanism(s) for efficient activation. Results: We here show that mutant CD8+ T cells lacking the IFN-α/β signalling components are hyporesponsive to antigen stimulation in vitro. We further show that IFN-α/β-mediated signals are required for induction of the chemokines IP-10/ITAC and their common receptor, CXCR3, and in turn provide evidence that CXCR3-mediated signals indeed function in the activation and proliferation of CD8+ T cells, particularly for the CD44low naive phenotype cells. Conclusion: The CXCR3 chemokine system is regulated by IFN-α/β in CD8+T cells, and it is critical for the efficient cell activation. The present study therefore reveals a novel role of the IFN-α/β-CXCR3 signalling cascade in CD8+T cell activation.