AXL drives regulatory cDC1 maturation to control CD8 T cell contraction during severe influenza recovery 2267518

Abstract Introduction Axl-dependent activation of XCR1+ cDC (cDC1) leads to regulatory maturation of cDC1 (mregDC1). After IAV infection, mature cDC1 dampen CD8 T cell function, however it is unknown whether this process is Axl-dependent. Methods We generated a mouse strain with a conditional deletion of Axl on Zbtb46-expressing cells (zDC-Axl). The transcriptome of cDC1 was analyzed by scRNA-seq. cDC1 phenotype, apoptotic cell acquisition, and cytokine production was analyzed by flow cytometry. Results Compared to naïve or infected lungs, the transcriptome of cDC1 from lungs in the resolution of IAV infection uniquely upregulates Actn1, Arg2 and Elmo1, genes associated with engulfment and processing of apoptotic cells (AC). The absence of Axl in cDCs resulted in diminished AC engulfment and the loss of PD-L1 and PD-L2 expression on cDC1. In vivo, transfer of Axl-deficient cDC1 failed to reduce the number of effector CD8 T cells. To test the function of Axl-deficient cDC1 in vitro, we sorted cDC1 from the lungs of infected mice in the resolution phase of infection and set up co-cultures with OT-I cells. Compared to WT cDC1, the Axl-/- cDC1 failed to inhibit the production of effector cytokines IFN and Granzyme B, both in effector and naïve OT-I cells. Conclusion Overall, our data show that Axl is required for the acquisition of AC and differentiation and function of mature regulatory cDC1 during the recovery phase of IAV infection. Funding Source N/A Topic Categories Immune Response Regulation: Cellular Mechanisms (IRC)