Bat3 regulates T cell terminal differentiation in an mTORC2-dependent manner

Human leukocyte antigen B (HLA-B)-associated transcript 3 (Bat3), also called Bcl-2-associated athanogene 6 (BAG6), is a multifunctional adapter protein that was previously shown to bind to the cytoplasmic tail of the checkpoint inhibitor Tim-3 and inhibit its downstream signaling pathway. Using mouse genetic models, we now demonstrate that deficiency of Bat3 selectively in T cells elicits a profound exhaustion phenotype and dampens autoreactive T cell-mediated neuroinflammation. Mechanistically, Bat3 acts as a critical mTORC2 inhibitor to suppress Akt function. As a result, Bat3 deficiency leads to increased Akt activity, and FOXO1 phosphorylation, indirectly promoting Prdm1. Transcriptional analysis of myelin antigen-specific CNS-infiltrating Bat3 deficient CD4 T cells revealed upregulation of dysfunction-associated genes concomitant with downregulation of genes associated with T cell effector function. Genes upregulated in Bat3cko T cells were significantly enriched for Prdm1(BLIMP1) and exhaustion gene signatures suggesting the absence of Bat3 can trigger T cell dysfunction even under highly inflammatory autoimmune conditions. Taken together, in this paper we identify a novel mechanism by which Bat3 not only directly suppresses Tim-3 signaling, but also plays a critical role in controlling the mTORC2-Akt-Blimp-1 pathway thereby suppressing the induction of the co-inhibitory module and preventing terminal differentiation and dysfunction of T cells. RNA-Seq comparision of Bat3cKO and Tim3cKO CNS-infiltrating Th1 cells from mice undergoing EAE.