June 24, 2022

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Nature: Tumor checkpoint immunotherapy relies on “dry-like” CD8+ T cells

Nature: Tumor checkpoint immunotherapy relies on “dry-like” CD8+ T cells


Nature: Tumor checkpoint immunotherapy relies on “dry-like” CD8+ T cells.   Long-term pathogen and tumor control and checkpoint immunotherapy rely on “stem-like” CD8+ T cells. The new results reveal that BACH2 is a key regulator of this subgroup and solve an important problem.

Based on this, Yao and his colleagues published a paper titled “BAtCHing stem-like T cells during exhaustion” in the journal Nature Immunology, revealing that the transcription repressor BACH2 establishes the epigenetic and genetic characteristics of Texstem cells after chronic viral infection. Transcribe the landscape.

Nature: Tumor checkpoint immunotherapy relies on "dry-like" CD8+ T cells

Although Texstem cells are known to use transcriptional regulators that overlap with those expressed in memory CD8+ T cells after acute infection or immunization, they also exhibit specific transcriptional and epigenetic characteristics of Tex cells.

Importantly, recent studies have shown that Texstem cells appear within a few days after infection with a fast-spreading persistent pathogen, and TCF-1-mediated suppression of competitive end effector-like fate (Teff-like) is essential for the early establishment of Texstem cell.

Given that transcription factors (TFs) are often part of complex molecular circuits, there is still an important question: which are the key nodes that promote the fate of Texstem cells and its unique epigenetic and transcriptional network in the early post-infection period?

Next, Yao et al. performed epigenetic and transcriptional data on the more terminally differentiated CD8+ T cells from Texstem cells and from mice that had been infected with lymphocytic choriomeningitis virus (LCMV) for a week. Meta-analysis.

This method identified several TFs whose DNA binding motifs are highly enriched in genomic regions with differential H3K27ac content or differential chromatin accessibility, and therefore can represent potential regulators of Texstem cell differentiation. Among them, the genes encoding the transcription repressor BACH2 and TFs TCF-1 and Jun also showed higher expression in Texstem cells.

Similar to what was described during an acute viral infection, where the suppression of memory genes allows the development of effector T cell responses, the above analysis indicated that BACH2 cultivates Texstem cells by suppressing the Texterm gene.

Finally, Yao and his collaborators found that BACH2 promotes the expression of characteristic transcriptional features of Texstem cells, while inhibiting Texterm-related genes in a subset of Texstem cells.

This includes BACH2-mediated up-regulation of TFs, such as Lef1, which encodes Lef1 and usually works with TCF-1, raising the possibility that BACH2 and TCF-1 may be part of the feedforward transcription loop, which will The recently activated CD8+ T cells polarize to the Texstem phenotype and inhibit their differentiation into Texterm cells.

Interestingly, it has been shown that T cell antigen receptor (TCR) signals inhibit BACH2 activity through post-translational modification, which seems to be inconsistent with the increased differentiation of Texstem cells in the presence of a large number of antigens early after infection.

The possible explanation is that the expression of PD-1 and PD-L1 effectively induced in the presence of high antigen load in turn counteracts the downstream inhibition of TCR signal transduction and the resulting BACH-2 activity, thereby facilitating the differentiation of Texstem cells.

In summary, the research of Yao et al. proved the key role of BACH2 in the commitment of the Texstem pedigree, but how does it accomplish this? BACH2 acts as an epigenetic regulator; it increases the chromatin accessibility of the loci associated with the cell fate of Texstem, and at the same time induces a closed chromatin state in Texterm-related regions.

For example, BACH2 makes chromatin inaccessible in regions containing the binding motifs of TFs RUNX3 and BATF, which have been shown to combat BACH2 activity and Texstem cell production early after infection. Importantly, the authors used the double knockout method to prove that in the absence of RUNX3, Texstem cell fate is not affected by BACH2 defects, indicating that RUNX3 acts downstream of BACH2. Yao et al. also identified BACH2 binding motifs in the open chromatin region of genes encoding TFs BLIMP-1 and BATF.

As mentioned above for RUNX3, the authors show that in the absence of BLIMP-1, BACH2 deficiency results in the same proportion of Texstem cells. Therefore, the study by Yao et al. proposed a model in which BACH2 establishes the best epigenetic and transcriptional landscape promised by Texstem cells by antagonizing the TF that promotes text cells through two different mechanisms:

(1) directly inhibiting their expression, As in the case of BLIMP-1 and BATF,

(2) restrict access to their regulatory areas, such as RUNX3 and BATF.

Given that TCR stimulation promotes RUNX3 activity and RUNX3 drives BLIMP-1 expression after acute infection, this model is also consistent with the aforementioned key role of BACH2 in promoting Texstem cell fate by controlling TCR signaling and downstream gene expression.

It is worth noting that RUNX3 has been shown to inhibit the expression of TCF-1 and BACH2, which indicates that RUNX3 may promote text cell differentiation by silencing BACH2 or TCF-1, otherwise BACH2 or TCF-1 will promote stem cell differentiation. 

Nature: Tumor checkpoint immunotherapy relies on "dry-like" CD8+ T cells

In the early stage of chronic viral infection, Bach2 promotes the differentiation of CD8+ T cells into Texstem cells through epigenetic and transcriptional mechanisms, while antagonizing the fate of TexTerm cells, doi.org/10.1038/s41590-021-00891-8


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