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

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.

 

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.

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.

 

MYB

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.)