TGF-β promotes stem-like T cells via enforcing their lymphoid tissue retention

Ma, Chaoyu; Wang, Liwen; Liao, Wei; Liu, Yong; Mishra, Shruti; Li, Guo; Zhang, Xin; Qiu, Yuanzheng; Lu, Qianjin; Zhang, Nu

doi:10.1084/jem.20211538

Cited by 19 publications

(11 citation statements)

References 45 publications

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“…Given the elevated expression of HIF-1α and its target genes in Tpex and transitory T cells during chronic viral infection, we speculate that HIF-1a signaling initiates terminal T cell differentiation via transcriptional-metabolic reprogramming from mitochondrial respiration to aerobic glycolysis. This notion is supported by recent studies demonstrating a decisive role of TGF-ý in maintaining Tpex cells 25, 66, 67 . TGF-ý inhibits the transition of Tpex into terminally differentiated Tex cells by suppressing mechanistic target of rapamycin (mTOR) and glycolytic reprogramming 25, 66, 68 .…”

Section: Discussionsupporting

confidence: 53%

HIF-1α-mediated mitochondrial-glycolytic reprogramming controls the transition of precursor to terminally exhausted T cells

Wu,

Zhao,

Hochrein

et al. 2023

Preprint

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Functional exhaustion of T cells in cancer and persistent infections is characterized by the upregulation of inhibitory receptors, the progressive decline in cytokine secretion and impaired cytolytic activity. Terminally exhausted T cells are steadily replenished by a precursor population (Tpex) with phenotypic features of memory T cells and a stem-like capacity to self-renew. However, the metabolic principles of Tpex maintenance and the regulatory circuits that control the exhaustion of their progeny remain incompletely understood. Using a combination of gene-deficient mice, single-cell transcriptomics and metabolomic analyses, we here show that mitochondrial insufficiency is a cell-intrinsic trigger that initiates the T cell exhaustion program. At the molecular level, we found that diminished mitochondrial respiration and metabolic remodeling cause oxidative stress, which inhibits the proteasomal degradation of hypoxia inducible factor 1 alpha (HIF-1α) in Tpex cells. HIF-1α mediates the transcriptional-glycolytic reprogramming of Tpex cells as an initial step towards terminal differentiation and functional exhaustion. Finally, we show that enhancing respiration by limiting the glycolytic activity of CAR T cells is a feasible metabolic intervention strategy to preserve the stemness of Tpex cells during chronic viral infection and cancer immunotherapy.

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Section: Discussionsupporting

confidence: 53%

HIF-1α-mediated mitochondrial-glycolytic reprogramming controls the transition of precursor to terminally exhausted T cells

Wu,

Zhao,

Hochrein

et al. 2023

Preprint

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“…Importantly, our findings emphasize the two unique features of TDLNs in tumor immunotherapies, i.e., (1) TDLNs function as a reservoir to host stemlike T cells and (2) TDLNs function as a trap to limit the active migration/differentiation of stem-like T cells. Similar to tumor settings, we have recently demonstrated that TGF-β promotes the retention of stem-like CD8 + T cells inside lymphoid follicles during chronic viral infection 50,51 . Thus, the TGF-β-dependent lymphoid tissue residency program is not tumor-specific and may represent a universal feature for Tcf-1 + CD8 + T cells.…”

Section: Discussionmentioning

confidence: 94%

TGF-β-dependent lymphoid tissue residency of stem-like T cells limits response to tumor vaccine

et al. 2022

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TGF-β signaling is necessary for CD8+ T cell differentiation into tissue resident memory T cells (TRM). Although higher frequency of CD8+ TRM cells in the tumor microenvironment is associated with better prognosis, TGF-β−blockade typically improves rather than worsens outcomes. Here we show that in a mouse melanoma model, in the tumor-draining lymph nodes (TDLN) rather than in the tumors themselves, stem-like CD8+ T cells differentiate into TRMs in a TGF-β and tumor antigen dependent manner. Following vaccination against a melanoma-specific epitope, most tumour-specific CD8+ T cells are maintained in a stem-like state, but a proportion of cells lost TRM status and differentiate into CX3CR1+ effector CD8+ T cells in the TDLN, which are subsequently migrating into the tumours. Disruption of TGF-β signaling changes the dynamics of these developmental processes, with the net result of improving effector CD8+ T cell migration into the tumours. In summary, TDLN stem-like T cells transiently switch from a TGF-β-dependent TRM differentiation program to an anti-tumor migratory effector development upon vaccination, which transition can be facilitated by targeted TGF-β blockade.

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“…First, TGF-β restrains mTOR (Mammalian Target of Rapamycin) activity in stem-like T cells to maintain their long-term responsiveness ( 64 ). Second, TGF-β directly suppress the differentiation of CX3CR1 + effector T cells and promotes the formation of CD101 + terminally exhausted T cells ( 64 , 66 , 67 ). Importantly, the impacts of TGF-β are significantly enhanced during the later stages of chronic infection ( 66 ).…”

Section: Lymphoid Residency Of Stem-like T Cells—chronic Infectionmentioning

confidence: 99%

“…Forcing TGF-βR deficient stem-like T cells to stay inside lymphoid follicles via integrin α4 blocking partially corrects the defects. This result suggests that manipulating the location of Tcf-1 + T cells alone is sufficient to control their differentiation ( 67 ).…”

Section: Lymphoid Residency Of Stem-like T Cells—chronic Infectionmentioning

confidence: 99%

Lymphoid tissue residency: A key to understand Tcf-1+PD-1+ T cells

Zhang

2022

Front. Immunol.

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During chronic antigen exposure, a subset of exhausted CD8+ T cells differentiate into stem cell-like or progenitor-like T cells expressing both transcription factor Tcf-1 (T cell factor-1) and co-inhibitory receptor PD-1. These Tcf-1+ stem-like or progenitor exhausted T cells represent the key target for immunotherapies. Deeper understanding of the biology of Tcf-1+PD-1+ CD8+ T cells will lead to rational design of future immunotherapies. Here, we summarize recent findings about the migratory and resident behavior of Tcf-1+ T cells. Specifically, we will focus on TGF-β-dependent lymphoid tissue residency program of Tcf-1+ T cells, which may represent a key to understanding the differentiation and maintenance of Tcf-1+ stem-like CD8+ T cells during persistent antigen stimulation.

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TGF-β promotes stem-like T cells via enforcing their lymphoid tissue retention

Cited by 19 publications

References 45 publications

HIF-1α-mediated mitochondrial-glycolytic reprogramming controls the transition of precursor to terminally exhausted T cells

HIF-1α-mediated mitochondrial-glycolytic reprogramming controls the transition of precursor to terminally exhausted T cells

TGF-β-dependent lymphoid tissue residency of stem-like T cells limits response to tumor vaccine

Lymphoid tissue residency: A key to understand Tcf-1+PD-1+ T cells

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