Xcr1, the receptor of XCL1, is expressed by a dendritic cell subpopulation [3]. The XCL1-XCR1 axis plays a vital role in dendritic-cell-mediated cytotoxic immune response, and also regulates thymic self-tolerance and regulatory T-cell generation [3].

Depletion of XCR1+ type 1 conventional dendritic cells (cDC1) in XCR1DTA mice or using anti-XCL1-blocking antibody attenuated liver pathology in non-alcoholic steatohepatitis (NASH) mouse models, indicating XCR1+ cDC1 are important drivers of liver pathology in NASH [1]. In chronic LCMV infection mouse models, exploiting XCR1+ DCs via Flt3L-mediated expansion or XCR1-targeted vaccination reinvigorates CD8+ T cells and improves virus control. Also, XCR1+ DCs are crucial for the success of checkpoint inhibitor-based therapies through differential activation of exhausted CD8+ T-cell subsets [2]. Knockout of XCR1 in chickens prevented the clustering of cDCs with CD8+ T-cells, suggesting a conserved role for XCR1+ cDCs in driving CD8+ T-cell responses [4]. Post-myocardial infarction (MI) depletion of XCR1+ cDC1 cells in mice suppressed CXCR3+ Th1 cell activation and prevented cardiac dysfunction, identifying a critical role of XCR1+ cDC1-activated CXCR3+ Th1 cells in ischemic cardiac remodeling [5].

In conclusion, Xcr1 is essential in dendritic-cell-mediated immune responses. Studies using gene knockout (KO) or conditional knockout (CKO) mouse models have revealed its significant roles in diseases such as NASH, chronic viral infections, and cardiac remodeling after ischemic myocardial injury, providing insights into disease mechanisms and potential therapeutic targets.