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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE168435 | GEO | 2021/04/30

REPOSITORIES: GEO

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Project description:Exhaustion markers are expressed by T lymphocytes in Follicular Lymphoma (FL). Through these, TIM-3 has been recently identified as a poor pronostic factor when expressed by FL CD4+ T cells. Before this study, there was no molecular characterization of unstimulated CD8+ T cells, expressing - or not - TIM-3. We used microarrays to compare the global gene expression profile between CD8+TIM-3+ T cells and CD8+TIM-3- T cells freshly sorted from follicular lymphoma biopsies. Abstract from the associated publication: Up-regulation of T-cell immunoglobulin-3 (TIM-3) has been associated with negative regulation of the immune response in chronic infection and cancer, including lymphoma. Here, we investigated the possible correlation between TIM-3 expression by ex vivo cytotoxic T cells (CTL) from follicular lymphoma (FL) biopsies and their functional unresponsiveness that could limit the favorable impact of CTL on disease progression. We report a high percentage of CD8+TIM-3+ T cells in lymph nodes of FL patients. When compared to their CD8+TIM-3- counterparts, CD8+TIM-3+ T cells exhibited defective cytokine production following TCR engagement. Furthermore CD8+TIM-3+ T cells display ex vivo markers of lytic granule release and remain unresponsive to further TCR-induced activation of the lytic machinery. Although confocal microscopy showed that TIM-3 expression on CD8+ T cells correlated with minor alterations of immunological synapse, a selective reduction of ERK signaling in CD8+TIM-3+ T cells was observed by phospho-flow analysis. Finally, short relapse free survival despite rituximab(R)-chemotherapy was observed in patients with high content of TIM-3+ cells and a poor infiltrate of granzyme B+ T cells in FL lymph nodes. Together, our data indicate that, besides selective TCR early signaling defects, TIM-3 expression correlates with unresponsiveness of ex vivo CD8+ T cells in FL. They show that scores based on the combination of exhaustion and cytolytic markers in FL microenvironment might be instrumental to identify patients at early risk of relapses following R-chemotherapy.

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

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