XCR1+DCs are critical for T cell-mediated immunotherapy of chronic viral infections

The contribution of cross-presenting XCR1+ dendritic cells (DCs) and SIRPa+ DCs in maintaining T cell function during exhaustion and immunotherapeutic interventions of chronic infections remains poorly characterized. Using the mouse model of chronic LCMV infection, we found that XCR1+ DCs are more resistant to infection and highly activated compared with SIRPa+ DCs. Exploiting XCR1+ DCs via Flt3L-mediated expansion or XCR1-targeted vaccination notably reinvigorates CD8+ T cells and improves virus control. Upon PD-L1 blockade, XCR1+ DCs are not required for the proliferative burst of progenitor exhausted CD8+ T (TPEX) cells but are indispensable to sustain the functionality of exhausted CD8+ T (TEX) cells. Combining anti-PD-L1 ther-apy with increased frequency of XCR1+ DCs improves functionality of TPEX and TEX subsets, while increase of SIRPa+ DCs dampened their proliferation. Together, this demonstrates that XCR1+ DCs are crucial for the suc-cess of checkpoint inhibitor-based therapies through differential activation of exhausted CD8+ T cell subsets.

Automated summary

The contribution of XCR1+ dendritic cells (DCs) and SIRPa+ DCs in maintaining T cell function during exhaustion and immunotherapeutic interventions of chronic infections is poorly understood. In a mouse model of chronic LCMV infection, XCR1+ DCs were found to be more resistant to infection and highly activated compared to SIRPa+ DCs. Exploiting XCR1+ DCs through expansion or vaccination improved CD8+ T cell functionality and virus control. PD-L1 blockade was found to be more effective when combined with increased frequency of XCR1+ DCs, enhancing the functionality of exhausted CD8+ T cell subsets.