CD8α+ Dendritic Cells Dictate Leukemia-Specific CD8+ T Cell Fates

Abstract

APCs are essential for the orchestration of antitumor T cell responses. Batf3-lineage CD8α⁺ and CD103⁺ dendritic cells (DCs), in particular, are required for the spontaneous initiation of CD8⁺ T cell priming against solid tumors. In contrast, little is known about the APCs that regulate CD8⁺ T cell responses against hematological malignancies. Using an unbiased approach, we aimed to characterize the APCs responsible for regulating CD8⁺ T cell responses in a syngeneic murine leukemia model. We show with single-cell resolution that CD8α⁺ DCs alone acquire and cross-present leukemia Ags in vivo, culminating in the induction of leukemia-specific CD8⁺ T cell tolerance. Furthermore, we demonstrate that the mere acquisition of leukemia cell cargo is associated with a unique transcriptional program that may be important in regulating tolerogenic CD8α⁺ DC functions in mice with leukemia. Finally, we show that systemic CD8α⁺ DC activation with a TLR3 agonist completely prevents their ability to generate leukemia-specific CD8⁺ T cell tolerance in vivo, resulting instead in the induction of potent antileukemia T cell immunity and prolonged survival of leukemia-bearing mice. Together, our data reveal that Batf3-lineage DCs imprint disparate CD8⁺ T cell fates in hosts with solid tumors versus systemic leukemia.