MYB orchestrates T cell exhaustion and response to checkpoint inhibition, Tsui, 2022

[Hutan]

https://www.nature.com/articles/s41586-022-05105-1

Abstract
CD8+ T cells that respond to chronic viral infections or cancer are characterized by the expression of inhibitory receptors such as programmed cell death protein 1 (PD-1) and by the impaired production of cytokines. This state of restrained functionality—which is referred to as T cell exhaustion1,2—is maintained by precursors of exhausted T (TPEX) cells that express the transcription factor T cell factor 1 (TCF1), self-renew and give rise to TCF1− exhausted effector T cells3,4,5,6.

Here we show that the long-term proliferative potential, multipotency and repopulation capacity of exhausted T cells during chronic infection are selectively preserved in a small population of transcriptionally distinct CD62L+ TPEX cells. The transcription factor MYB is not only essential for the development of CD62L+ TPEX cells and maintenance of the antiviral CD8+ T cell response, but also induces functional exhaustion and thereby prevents lethal immunopathology. Furthermore, the proliferative burst in response to PD-1 checkpoint inhibition originates exclusively from CD62L+ TPEX cells and depends on MYB.

Our findings identify CD62L+ TPEX cells as a stem-like population that is central to the maintenance of long-term antiviral immunity and responsiveness to immunotherapy. Moreover, they show that MYB is a transcriptional orchestrator of two fundamental aspects of exhausted T cell responses: the downregulation of effector function and the long-term preservation of self-renewal capacity.

 

[Hutan]

Department of Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, Victoria, Australia

Institute for Medical Microbiology, Immunology and Hygiene, School of Medicine, Technical University of Munich (TUM), Munich, Germany

This paper is difficult for me, but it seems that the authors are saying they have discovered a new form of t-cell that helps the body live with a chronic infection without incurring damage from an anti-pathogen campaign.

Overall, our data show that the CD8+ T cell response in chronic infection is maintained by a small population of distinct TPEX cells that co-express TCF1, CD62L and the transcription factor MYB. These cells, which we term stem-like exhausted T (TSLEX) cells here, possess superior self-renewal, multipotency and long-term proliferative capacity compared to their TCF1+ but CD62L− descendants. Loss of MYB abrogated the differentiation of TSLEX cells and severely impaired the the persistence of the entire TCF1+ TPEX cell compartment, ultimately resulting in the collapse of the complete CD8+ T cell response. MYB also mediates functional exhaustion during chronic infection by restricting the initial expansion and effector function of antigen-responsive CD8+ effector T cells. As a result, mice that lacked MYB in their T cells succumbed to chronic but not acute viral infection, highlighting that T cell exhaustion is an essential adaptation to chronic infection.

Thus, MYB represents a transcriptional checkpoint that instructs the differentiation and function of CD8+ T cells in response to severe or chronic infection. Our data also show that TSLEX cells are exclusively required to mediate the response to PD-1 checkpoint inhibition. These findings not only advance our understanding of the mechanisms of T cell re-invigoration in the context of checkpoint inhibition, but also emphasize the need for new therapeutic strategies that target TSLEX cells to harness the full potential of T cell-mediated immunotherapy. Furthermore, the superior proliferative and developmental potential of TSLEX cells makes them prime targets of adoptive T cell transfer and chimeric antigen receptor (CAR) T cell therapies. Finally, our results show that two central but seemingly unrelated properties of exhausted T cells—limited function and longevity—are intimately linked by a single transcription factor MYB; this is a notable example of evolutionary parsimony, which ensures ongoing T cell immunity during chronic infection while preventing collateral damage to the host.

I'd love this team to take a look at these cells in people with ME/CFS and Long Covid.

Perhaps these cells could be an indicator of a chronic infection, or at least of a body that thinks it has a chronic infection.

 

[Hutan]

Overall, our data show that the CD8+ T cell response in chronic infection is maintained by a small population of distinct TPEX cells that co-express TCF1, CD62L and the transcription factor MYB.

MYB

Transcriptional activator; DNA-binding protein that specifically recognize the sequence 5'-YAAC[GT]G-3'. Plays an important role in the control of proliferation and differentiation of hematopoietic progenitor cells.

Alternative splicing results in multiple transcript variants.

MYB is associated with some cancers, including leukemias, lymphomas and adenoid cystic carcinoma.



MYB was mentioned in this ME/CFS transcription study.

A Split Gender Pharmacogenomic Study of Gene Expression Modules in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Reveals Putative Treatment Avenues, 2019, Jeffrey et al
This study found the C-MYB transcription factor network was upregulated in females with ME/CFS, although MYB itself was not. (green indicates up-regulation)


(Just by the way, that figure from the Jeffrey paper also noted that genes associated with pathways affected in adenoid cystic carcinoma were upregulated.)

 

[Andy]

A Split Gender Pharmacogenomic Study of Gene Expression Modules in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Reveals Putative Treatment Avenues, 2019, Jeffrey et al
This study found the C-MYB transcription factor network was upregulated in females with ME/CFS, although MYB itself was not. (green indicates up-regulation)

Pretty sure this is our thread on this, Treatment avenues in ME/CFS: A split-gender pharmacogenomic study of gene-expression modules, 2019, Jeffrey, Broderick. Klimas et al