Regulatory maturation of cDC1 accelerates effector CD8 T cell contraction after severe influenza A virus infection.

Introduction/Rationale: XCR1+ dendritic cells (cDC1) initiate CD8 T cell responses against Influenza A virus (IAV) infection. In the resolution phase, sustained cytokine production by CD8 T cells prolong lung damage, however, whether cDC1 regulate effector CD8 T cells is unknown.

Methods: cDC1 and CD8 T cells were characterized by flow cytometry. The transcriptome of cDC1 populations was analyzed by scRNA-seq. To investigate the function of mature cDC1 we co-cultured lung cDC1 and OT-I cells, performed adoptive transfers of OT-I cells, and transplanted bone marrow (BM) into fluorescent mice.

Results: IAV infection triggered two rounds of cDC1 maturation. The first round during the acute infection and is followed by recruitment of effector CD8 T cells. The second round occurs in the resolution phase and is followed by contraction of antigen specific CD8 T cells. The transcriptome of mature cDC1 showed that cDC1 maturation is driven by TNFa and IFNg in naïve and infected mice respectively. In the resolution phase, mature cDC1 express genes related to efferocytosis and immunoregulation. Transplant of WT BM into fluorescent mice showed that cDC1 acquire apoptotic cells only in the resolution phase. Our in vivo and in vitro experiments showed that mature cDC1 from the resolution phase reduced T-bet and IFNg production in OT-I cells while expanding RORgt OT-I cells.

Conclusion: The mature cDC1 that accumulate in the lungs during the resolution phase of IAV infection regulate effector CD8 T cell responses.