XCR1+ DCs are critical for T cell-mediated immunotherapy of chronic viral infections
Eva Domenjo-Vila,
Valentina Casella,
Ryutaro Iwabuchi,
Even Fossum,
Mireia Pedragosa,
Quim Castellví,
Paula Cebollada Rica,
Tsuneyasu Kaisho,
Kazutaka Terahara,
Gennady Bocharov,
Jordi Argilaguet,
Andreas Meyerhans
Affiliations
Eva Domenjo-Vila
Infection Biology Laboratory, Department of Medicine and Life Sciences (MELIS), Universitat Pompeu Fabra, Barcelona, Spain
Valentina Casella
Infection Biology Laboratory, Department of Medicine and Life Sciences (MELIS), Universitat Pompeu Fabra, Barcelona, Spain
Ryutaro Iwabuchi
Department of Immunology, National Institute of Infectious Diseases, Tokyo, Japan; Department of Life Science and Medical Bioscience, Waseda University, Tokyo, Japan
Even Fossum
Department of Immunology, Division of Laboratory Medicine, Oslo University Hospital, Oslo, Norway
Mireia Pedragosa
Infection Biology Laboratory, Department of Medicine and Life Sciences (MELIS), Universitat Pompeu Fabra, Barcelona, Spain
Quim Castellví
Department of Information and Communication Technologies, Universitat Pompeu Fabra, Barcelona, Spain
Paula Cebollada Rica
Infection Biology Laboratory, Department of Medicine and Life Sciences (MELIS), Universitat Pompeu Fabra, Barcelona, Spain
Tsuneyasu Kaisho
Department of Immunology, Institute of Advanced Medicine, Wakayama Medical University, Wakayama, Japan
Kazutaka Terahara
Department of Immunology, National Institute of Infectious Diseases, Tokyo, Japan
Gennady Bocharov
Marchuk Institute of Numerical Mathematics, Russian Academy of Sciences, Moscow, Russia; Sechenov First Moscow State Medical University, Moscow, Russia
Jordi Argilaguet
Infection Biology Laboratory, Department of Medicine and Life Sciences (MELIS), Universitat Pompeu Fabra, Barcelona, Spain; IRTA, Centre de Recerca en Sanitat Animal (CReSA-IRTA-UAB), Campus de la Universitat Autònoma de Barcelona, Bellaterra, Spain; Corresponding author
Andreas Meyerhans
Infection Biology Laboratory, Department of Medicine and Life Sciences (MELIS), Universitat Pompeu Fabra, Barcelona, Spain; Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain; Corresponding author
Summary: 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.
