NR4a1/2 deletion promotes accumulation of TCF1+ stem-like precursors of exhausted CD8+ T cells in the tumor microenvironment

Srirat, Tanakorn; Hayakawa, Taeko; Mise-Omata, Setsuko; Nakagawara, Kensuke; Ando, Makoto; Shichino, Shigeyuki; Ito, Minako; Yoshimura, Akihiko

doi:10.1016/j.celrep.2024.113898

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2024

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Cited by 7 publications

References 56 publications

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T cell exhaustion and senescence for ovarian cancer immunotherapy

Zhao,

Wang,

Tian

et al. 2024

Seminars in Cancer Biology

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T cell exhaustion and senescence for ovarian cancer immunotherapy

Zhao,

Wang,

Tian

et al. 2024

Seminars in Cancer Biology

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CRISPR-Cas gene knockouts to optimize engineered T cells for cancer immunotherapy

De Castro,

Galaine,

Loyon

et al. 2024

Cancer Gene Ther

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A lymphoid tissue chemokine checkpoint prevents loss of CD8⁺T cell functionality

Altenburger,

Claudino Carvoeiro,

Dehio

et al. 2024

Preprint

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The generation of effector CD8+ T cells (TEFF) requires activation of naive CD8+ T cells (TN) by dendritic cells (DCs) within lymphoid tissue. To date, it remains elusive how the duration of TN-DC interactions and integration of activation signals are controlled in vivo. Here, we report that lymphoid stroma-secreted ligands for CCR7 constrained interaction duration by gradually inducing CD8+ T cell release from DCs. At late time points of interactions, CCR7 ligands repositioned the F-actin-promoting factor DOCK2 away from the DC interface to enable CD8+ T cell detachment, proliferation onset and acquisition of cytotoxicity. Lack of CCR7 signaling, as during ex vivo activation or in chronically inflamed lymphoid tissue, caused sustained T cell-DC interactions, and generated dysfunctional TEFF with high expression of inhibitory receptors, impaired antimicrobial activity, and poor recall responses. In sum, our findings uncover that lymphoid stromal chemokines act as built-in "disruptors" of T cell-DC interactions for long-term preservation of TEFF functionality.

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NR4a1/2 deletion promotes accumulation of TCF1+ stem-like precursors of exhausted CD8+ T cells in the tumor microenvironment

Cited by 7 publications

References 56 publications

T cell exhaustion and senescence for ovarian cancer immunotherapy

T cell exhaustion and senescence for ovarian cancer immunotherapy

CRISPR-Cas gene knockouts to optimize engineered T cells for cancer immunotherapy

A lymphoid tissue chemokine checkpoint prevents loss of CD8⁺T cell functionality

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NR4a1/2 deletion promotes accumulation of TCF1+ stem-like precursors of exhausted CD8+ T cells in the tumor microenvironment

Cited by 7 publications

References 56 publications

T cell exhaustion and senescence for ovarian cancer immunotherapy

T cell exhaustion and senescence for ovarian cancer immunotherapy

CRISPR-Cas gene knockouts to optimize engineered T cells for cancer immunotherapy

A lymphoid tissue chemokine checkpoint prevents loss of CD8+T cell functionality

Contact Info

Product

Resources

About

A lymphoid tissue chemokine checkpoint prevents loss of CD8⁺T cell functionality