A subset of mouse dendritic cells (DCs) specifically express the chemokine receptor XCR1 and excels at priming CD8+ T cells especially through cross-presentation. XCR1+ DCs are also highly efficient for the activation of natural killer (NK) cells and invariant NK T cells. XCL1, the ligand of XCR1, is selectively and strongly expressed by NK, NK T and activated or memory CD8+ T cells. Hence, we are investigating whether and how the XCL1->XCR1 axis regulates the cross-talk between cytotoxic lymphocyte subsets and XCR1+ DCs.

We have previously shown that the XCL1->XCR1 axis promotes early control of Listeria monocytogenes during primary infections of mice, by enhancing protective CD8+ T cell responses. Here we examined whether XCR1 deficiency affected NK cell responses to mouse cytomegalovirus (MCMV) infection. XCR1-deficient mice failed to control MCMV infection. This susceptibility was correlated to reduced production of IL-12 by XCR1+ DCs, and reduced NK cell activation and proliferation. Finally, in infected XCR1-deficient mice, NK cells and XCR1+ DCs failed to cluster together in the marginal zone of the spleen. Hence, signaling through XCR1 may orchestrate optimal interactions between XCR1+ DCs and NK cells, during MCMV infection, thereby promoting their mutual activation and the downstream control of viral replication.

Therefore, XCR1 plays a critical role in orchestrating the interactions of XCR1+ DCs both with innate and adaptive lymphocytes, and confers immunoregulatory functions to XCR1+ DCs in addition to their antigen-presenting functions.