MYB orchestrates T cell exhaustion and response to checkpoint inhibition

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 cells3–6. 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.

Early transcriptional and epigenetic divergence of CD8+ T cells responding to acute versus chronic infection

“…One possibility is that viral antigen load may be substantially higher at early time points in LCMV-Cl13 compared to LCMV-Arm infection, potentially leading to increased TCR signaling. In this study, we administered LCMV-Arm at 2 × 10 5 PFU IP and LCMV-Cl13 at 2 × 10 6 PFU IV as these infection doses and routes have been routinely used to model acute and chronic infections [ 34 , 35 ], respectively, but they may have resulted in differences in viral antigen loads. Moreover, it should be noted that even at identical doses and routes of infection, infection with LCMV-Cl13 resulted in higher proportions of infected plasmacytoid dendritic cells (pDCs) and higher levels of serum IFNα and IFNβ at 24 hours post-infection compared to infection with LCMV-Arm [ 36 , 37 ].…”

Transcriptional states of CAR-T infusion relate to neurotoxicity – lessons from high-resolution single-cell SOM expression portraying

“…Data of the isolated T cells and of the derived infusion product would be valuable to investigate proportions of cycling T cells and subsequent CAR positivity in a series of patients, helping to understand if the physiologic state of the T cells affects CAR transfer efficiency and to exclude putative genetic biases. Interestingly, association between proliferative activity, checkpoint inhibition, long-time responsiveness to immunotherapy and self-renewal capacity related to T-cell exhaustion was recently reported suggesting a complex and only partly understood relation between cell-cycle and T-cell function ( 52 ).…”

Tapping the keg of discovery to advance T cell therapy

“…We heard from Rafi Ahmed, Pablo Umana, Ira Mellman, Axel Kallies and several others about signals that contribute to the self-renewal and advancement of T cells along the developmental path towards terminal T cell exhaustion. In this section, new therapeutic tools exploiting IL-2 signaling were described in the context of modifying the fate commitment of progenitor exhausted T cells 2 – 4 (and unpublished data). Andrea Schietinger discussed T cell differentiation states and fate determinants in the chronic T cell-driven autoimmune disease type 1 diabetes 5 , and Vijay Kuchroo and Christina Zielinsky taught us about regulators of type 17 helper T (T H 17) cell fate 6 , 7 .…”