Tim-3 adapter protein Bat3 acts as an endogenous regulator of tolerogenic dendritic cell function

Abstract

Dendritic cells (DCs) sense environmental cues and adopt either an immune-stimulatory or regulatory phenotype, thereby fine-tuning immune responses. Identifying endogenous regulators that determine DC function can thus inform the development of therapeutic strategies for modulating the immune response in different disease contexts. Tim-3 plays an important role in regulating immune responses by inhibiting the activation status and the T cell priming ability of DC in the setting of cancer. Bat3 is an adaptor protein that binds to the tail of Tim-3; therefore, we studied its role in regulating the functional status of DCs. In murine models of autoimmunity (experimental autoimmune encephalomyelitis) and cancer (MC38-OVA–implanted tumor), lack of Bat3 expression in DCs alters the T cell compartment—it decreases T _H 1, T _H 17 and cytotoxic effector cells, increases regulatory T cells, and exhausted CD8 ⁺ tumor-infiltrating lymphocytes, resulting in the attenuation of autoimmunity and acceleration of tumor growth. We found that Bat3 expression levels were differentially regulated by activating versus inhibitory stimuli in DCs, indicating a role for Bat3 in the functional calibration of DC phenotypes. Mechanistically, loss of Bat3 in DCs led to hyperactive unfolded protein response and redirected acetyl–coenzyme A to increase cell intrinsic steroidogenesis. The enhanced steroidogenesis in Bat3-deficient DC suppressed T cell response in a paracrine manner. Our findings identified Bat3 as an endogenous regulator of DC function, which has implications for DC-based immunotherapies.

Abstract

Bat3 acts as a critical cell-intrinsic regulator of DC function.

How to Bat3r tolerate dendritic cells

Dendritic cells (DCs) are crucial components of immune responses, and their environment often dictates whether they are pro- or anti-inflammatory. Here, Tang et al. investigated the impact of Bat3, a protein that binds to Tim-3, in DC function in mouse models of experimental autoimmune encephalomyelitis (EAE) and cancer. Using mice with a knockout of Bat3 in DCs, they found that EAE was attenuated, but tumor growth was promoted. These effects were linked to a tolerogenic phenotype of Bat3 knockout DCs, which led to more anti-inflammatory T cells. Bat3 knockout in DCs was linked to an altered metabolic and unfolded protein response, leading to increased glucocorticoid production by DCs and subsequent T cell suppression. Thus, Bat3 regulates DC-mediated tolerance in the setting of autoimmunity and cancer.