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| Status |
Public on Apr 30, 2021 |
| Title |
Bat3 regulates T cell terminal differentiation in an mTORC2-dependent manner |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
|
| Summary |
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.
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| Overall design |
RNA-Seq comparision of Bat3cKO and Tim3cKO CNS-infiltrating Th1 cells from mice undergoing EAE.
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| |
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| Contributor(s) |
Zhu C, Dixon KO, Singer M, Kuchroo V |
| Citation(s) |
33931442 |
| |
| Submission date |
Mar 08, 2021 |
| Last update date |
May 19, 2021 |
| Contact name |
Meromit Singer |
| E-mail(s) |
msinger@broadinstitute.org
|
| Organization name |
Broad Institute of MIT and Harvard
|
| Street address |
415 main st, ROOM 6031
|
| City |
CAMBRIDGE |
| State/province |
MASSACHUSETTS |
| ZIP/Postal code |
02142 |
| Country |
USA |
| |
|
| Platforms (1) |
| GPL19057 |
Illumina NextSeq 500 (Mus musculus) |
|
| Samples (5)
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| Relations |
| BioProject |
PRJNA707416 |
| SRA |
SRP309701 |
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