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

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.

PD-1 regulates extrathymic regulatory T-cell differentiation.

Treg cells and the programed death-1/programed death ligand-1 (PD-1/PD-L1) pathway are both critical for maintaining peripheral tolerance to self-Ags. A significant subset of Treg cells constitutively expresses PD-1, which prompted an investigation into the role of PD-1/PD-L1 interactions in Treg-cell development, function, and induction in vivo. The phenotype and abundance of Treg cells was not significantly altered in PD-1-deficient mice. The thymic development of polyclonal and monospecific Treg cells was not negatively impacted by PD-1 deficiency. The suppressive function of PD-1(-/-) Treg cells was similar to their PD-1(+/+) counterparts both in vitro and in vivo. However, in three different in vivo experimental settings, PD-1(-/-) conventional CD4(+) T cells demonstrated a strikingly diminished tendency toward differentiation into peripherally induced Treg (pTreg) cells. Our results demonstrate that PD-1 is dispensable for thymic Treg-cell development and suppressive function, but is critical for the extrathymic differentiation of pTreg cells in vivo. These data suggest that Ab blockade of the PD-1/PD-L1 pathway may augment T-cell responses by acting directly on conventional T cells, and also by suppressing the differentiation of pTreg cells.

Calreticulin promotes immunity and type I interferon-dependent survival in mice with acute myeloid leukemia.

Exposure of cancer cells to particular chemotherapeutic agents or γ-irradiation induces a form of cell death that stimulates an immune response in mice. This "immunogenic cell death" requires calreticulin (CRT) translocation to the plasma membrane, which has been shown to promote cancer cell phagocytosis. However, it remains unclear whether the effect of CRT on cancer cell phagocytosis is alone sufficient to affect tumor immunity. Acute myeloid leukemia (AML) cells expressing cell-surface CRT were generated in order to characterize the mechanism(s) through which CRT activates tumor immune responses. Potent immune-mediated control or rejection of AML was observed in mice with CRT-expressing leukemia. The "CRT effect" was ultimately T-cell dependent, but dendritic cells (DCs), and CD8α+ DCs in particular, were also necessary, indicating that CRT might act directly on these DCs. CRT-expressing AML cells were slightly more susceptible to phagocytosis by DCs in vivo, but this effect was unlikely to explain the potent immunity observed. CRT did not affect classical DC maturation markers, but induced expression of type I interferon (IFN), which was critical for its positive effect on survival. In conclusion, CRT functions as a "danger signal" that promotes a host type I IFN response associated with the induction of potent leukemia-specific T-cell immunity.