Role of nuclear localization in the regulation and function of T-bet and Eomes in exhausted CD8 T cells

McLane, Laura M.; Ngiow, Shin Foong; Chen, Zeyu; Attanasio, John; Manne, Sasikanth; Ruthel, Gordon; Wu, Jennifer E.; Staupe, Ryan P.; Xu, Wei; Amaravadi, Ravi K.; Xu, Xiaowei; Karakousis, Giorgos C.; Mitchell, Tara C.; Schuchter, Lynn M.; Huang, Alexander C.; Freedman, Bruce D.; Betts, Michael R.; Wherry, E. John

doi:10.1016/j.celrep.2021.109120

Cited by 81 publications

(70 citation statements)

References 66 publications

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“…Distinct from SLECs and MPECs, T-bet and Eomes were shown to be dually required for CD8 + T ex development (41). In addition, these transcription factors appeared to arise at different stages of CD8 + T ex , where PD-1 lo T-bet lo CD8 + T ex were found to increase Eomes expression and sustain its nuclear localization, divide, and differentiate into PD-1 hi T-bet −/lo/hi Eomes hi CD8 + T ex (Figures 3B and 4A) (40,41,46). This differential usage of T-bet and Eomes also suggested that CD8 + T ex was a distinct lineage.…”

Section: Dawn Of Stem-like Precursors and Progenitors Of Exhausted Cd8 + T Cellsmentioning

confidence: 96%

“…It also became apparent that heterogeneity existed at a deeper level than surface PD-1, where CD8 + T ex appeared to use the same T-box family transcription factors, T-box expressed in T cells (T-bet) and eomesodermin (Eomes), for SLEC and MPEC lineage commitment, respectively, but with different expression patterns, nuclear localization, and developmental connectivity (4,(39)(40)(41). In response to TCR/MHC ligation and orientation of the immune synapse, a naïve CD8 + T cell will asymmetrically divide and unequally partition T-bet and Eomes, separately dictating effector versus memory fates from the first division (22,(42)(43)(44)(45).…”

Section: Dawn Of Stem-like Precursors and Progenitors Of Exhausted Cd8 + T Cellsmentioning

confidence: 99%

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CD8+ T Cell Exhaustion in Cancer

et al. 2021

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A paradigm shift in the understanding of the exhausted CD8+ T cell (Tex) lineage is underway. Originally thought to be a uniform population that progressively loses effector function in response to persistent antigen, single-cell analysis has now revealed that CD8+ Tex is composed of multiple interconnected subpopulations. The heterogeneity within the CD8+ Tex lineage is comprised of immune checkpoint blockade (ICB) permissive and refractory subsets termed stem-like and terminally differentiated cells, respectively. These populations occupy distinct peripheral and intratumoral niches and are characterized by transcriptional processes that govern transitions between cell states. This review presents key findings in the field to construct an updated view of the spatial, transcriptional, and functional heterogeneity of anti-tumoral CD8+ Tex. These emerging insights broadly call for (re-)focusing cancer immunotherapies to center on the driver mechanism(s) underlying the CD8+ Tex developmental continuum aimed at stabilizing functional subsets.

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Section: Dawn Of Stem-like Precursors and Progenitors Of Exhausted Cd8 + T Cellsmentioning

confidence: 96%

Section: Dawn Of Stem-like Precursors and Progenitors Of Exhausted Cd8 + T Cellsmentioning

confidence: 99%

CD8+ T Cell Exhaustion in Cancer

et al. 2021

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“…Following acute infection, T-bet promotes terminal differentiation and represses inhibitory receptors during chronic viral infection. During chronic infection and in human tumors, T-bet is downregulated and it has been demonstrated that exhausted T-cells present a higher ratio of nuclear Eomes/T-bet, compared to memory T-cells [ 175 , 176 ]. High nuclear levels of T-bet repress Pdcd1 transcripts, while low nuclear levels in exhausted cells lead to a dominant effect of Eomes, which is a weaker repressor of Pdcd1.…”

Section: Factors Influencing T-cell Persistence In Clinical Settingsmentioning

confidence: 99%

“…High nuclear levels of T-bet repress Pdcd1 transcripts, while low nuclear levels in exhausted cells lead to a dominant effect of Eomes, which is a weaker repressor of Pdcd1. In fact, T-bet and Eomes compete for the same binding motifs, including the Pdcd1 T-box (PD-1 gene) [ 175 ]. Not only T-bet directly represses Pdcd1 , but it was also shown to decrease other inhibitory receptors.…”

Section: Factors Influencing T-cell Persistence In Clinical Settingsmentioning

confidence: 99%

Improving CAR T-Cell Persistence

Pietrobon

Todd

Goswami

et al. 2021

IJMS

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Over the last decade remarkable progress has been made in enhancing the efficacy of CAR T therapies. However, the clinical benefits are still limited, especially in solid tumors. Even in hematological settings, patients that respond to CAR T therapies remain at risk of relapsing due to several factors including poor T-cell expansion and lack of long-term persistence after adoptive transfer. This issue is even more evident in solid tumors, as the tumor microenvironment negatively influences the survival, infiltration, and activity of T-cells. Limited persistence remains a significant hindrance to the development of effective CAR T therapies due to several determinants, which are encountered from the cell manufacturing step and onwards. CAR design and ex vivo manipulation, including culture conditions, may play a pivotal role. Moreover, previous chemotherapy and lymphodepleting treatments may play a relevant role. In this review, the main causes for decreased persistence of CAR T-cells in patients will be discussed, focusing on the molecular mechanisms underlying T-cell exhaustion. The approaches taken so far to overcome these limitations and to create exhaustion-resistant T-cells will be described. We will also examine the knowledge gained from several key clinical trials and highlight the molecular mechanisms determining T-cell stemness, as promoting stemness may represent an attractive approach to improve T-cell therapies.

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“…However, it has recently been demonstrated that not only Eomes expression, but also its subcellular localization influences the degree of T cell exhaustion: when present within the nucleus, Eomes regulates PD-1 expression by competing with the transcription factor Tbet for binding to Tbox sequences. Thus, a high Eomes:Tbet ratio can enhance PD-1 expression, since Eomes is a weaker PD-1 repressor than Tbet [16].…”

Section: Introductionmentioning

confidence: 99%

Unraveling the Multifaceted Nature of CD8 T Cell Exhaustion Provides the Molecular Basis for Therapeutic T Cell Reconstitution in Chronic Hepatitis B and C

Barili

Vecchi

Rossi

et al. 2021

Cells

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In chronic hepatitis B and C virus infections persistently elevated antigen levels drive CD8+ T cells toward a peculiar differentiation state known as T cell exhaustion, which poses crucial constraints to antiviral immunity. Available evidence indicates that T cell exhaustion is associated with a series of metabolic and signaling deregulations and with a very peculiar epigenetic status which all together lead to reduced effector functions. A clear mechanistic network explaining how intracellular metabolic derangements, transcriptional and signaling alterations so far described are interconnected in a comprehensive and unified view of the T cell exhaustion differentiation profile is still lacking. Addressing this issue is of key importance for the development of innovative strategies to boost host immunity in order to achieve viral clearance. This review will discuss the current knowledge in HBV and HCV infections, addressing how innate immunity, metabolic derangements, extensive stress responses and altered epigenetic programs may be targeted to restore functionality and responsiveness of virus-specific CD8 T cells in the context of chronic virus infections.

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Role of nuclear localization in the regulation and function of T-bet and Eomes in exhausted CD8 T cells

Cited by 81 publications

References 66 publications

CD8+ T Cell Exhaustion in Cancer

CD8+ T Cell Exhaustion in Cancer

Improving CAR T-Cell Persistence

Unraveling the Multifaceted Nature of CD8 T Cell Exhaustion Provides the Molecular Basis for Therapeutic T Cell Reconstitution in Chronic Hepatitis B and C

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