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

Domenjó Vila, Eva, 1993-; Casella, Valentina, 1991-; Iwabuchi, Ryutaro; Fossum, Even; Pedragosa Marín, Mireia, 1988-; Castellví Fernández, Quim; Cebollada Rica, Paula; Kaisho, Tsuneyasu; Terahara, Kazutaka; Bocharov, Gennady A.; Argilaguet Marqués, Jordi, 1977-; Meyerhans, Andreas

doi:http://dx.doi.org/10.1016/j.celrep.2023.112123

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

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Domenjo-Vila E, Casella V, Iwabuchi R, Fossum E, Pedragosa M, Castellví Q, Cebollada Rica P, Kaisho T, Terahara K, Bocharov G, Argilaguet J, Meyerhans A. XCR1+ DCs are critical for T cell-mediated immunotherapy of chronic viral infections. Cell Rep. 2023 Feb 14;42(2):112123. DOI: 10.1016/j.celrep.2023.112123

Abstract

The contribution of cross-presenting XCR1+ dendritic cells (DCs) and SIRPα+ 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 SIRPα+ 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 therapy with increased frequency of XCR1+ DCs improves functionality of TPEX and TEX subsets, while increase of SIRPα+ DCs dampened their proliferation. Together, this demonstrates that XCR1+ DCs are crucial for the success of checkpoint inhibitor-based therapies through differential activation of exhausted CD8+ T cell subsets.