FOXP3 renders activated human regulatory T cells resistant to restimulation-induced cell death by suppressing SAP expression

Katz, Gil; Voss, Kelsey; Yan, Toria F.; Kim, Yong Chan; Kortum, Robert L.; Scott, David W.; Snow, Andrew L.

doi:10.1016/j.cellimm.2018.02.007

Cited by 13 publications

(14 citation statements)

References 48 publications

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“…We initially hypothesized that FOXP3 protects expanding Tcons from RICD by suppressing SAP expression, similar to Tregs. 18 Surprisingly, FOXP3 KD cells showed no increase in SAP expression relative to controls ( Fig. 2a).…”

Section: Foxp3 Knockdown Does Not Impact T-cell Proliferation or Sap mentioning

confidence: 89%

“…Tregs are highly resistant to RICD due to FOXP3-dependent repression of SAP. 18,21 In this study, we determined whether transient FOXP3 upregulation protects newly activated Tcons from RICD. Indeed, our results show for the first time that FOXP3 also modulates RICD sensitivity in a proportion of both CD4 and CD8 human Tcons through a novel, SAP-independent mechanism involving CD48 upregulation and augmented autophagy.…”

Section: Discussionmentioning

confidence: 99%

“…Forkhead box P3 (FOXP3) + -regulatory CD4 T cells (Tregs) express low levels of SAP, and are extremely resistant to RICD compared with conventional T cells (Tcons; i.e., non-Tregs), 18 in part because of TGF-β1 signaling. 19,20 FOXP3 induces RICD resistance in activated human Tregs, 18,21 and we recently showed that FOXP3 directly represses SAP transcription to confer resistance. 18 Human Tcons also express FOXP3 transiently after TCR activation, 22 but FOXP3 function in this context remains mysterious, as it does not confer a Treg-like suppressive phenotype.…”

Section: Introductionmentioning

confidence: 99%

“…19,20 FOXP3 induces RICD resistance in activated human Tregs, 18,21 and we recently showed that FOXP3 directly represses SAP transcription to confer resistance. 18 Human Tcons also express FOXP3 transiently after TCR activation, 22 but FOXP3 function in this context remains mysterious, as it does not confer a Treg-like suppressive phenotype. 23,24 FOXP3 may curb proliferation and cytokine production in human Tcons, 25,26 but studies have shown inconsistent results.…”

Section: Introductionmentioning

confidence: 99%

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FOXP3 protects conventional human T cells from premature restimulation-induced cell death

et al. 2019

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The adaptive immune response relies on specific apoptotic programs to maintain homeostasis. Conventional effector T cell (Tcon) expansion is constrained by both forkhead box P3 (FOXP3) +-regulatory T cells (Tregs) and restimulation-induced cell death (RICD), a propriocidal apoptosis pathway triggered by repeated stimulation through the T-cell receptor (TCR). Constitutive FOXP3 expression protects Tregs from RICD by suppressing SLAM-associated protein (SAP), a key adaptor protein that amplifies TCR signaling strength. The role of transient FOXP3 induction in activated human CD4 and CD8 Tcons remains unresolved, but its expression is inversely correlated with acquired RICD sensitivity. Here, we describe a novel role for FOXP3 in protecting human Tcons from premature RICD during expansion. Unlike FOXP3-mediated protection from RICD in Tregs, FOXP3 protects Tcons through a distinct mechanism requiring de novo transcription that does not require SAP suppression. Transcriptome profiling and functional analyses of expanding Tcons revealed that FOXP3 enhances expression of the SLAM family receptor CD48, which in turn sustains basal autophagy and suppresses pro-apoptotic p53 signaling. Both CD48 and FOXP3 expression reduced p53 accumulation upon TCR restimulation. Furthermore, silencing FOXP3 expression or blocking CD48 decreased the mitochondrial membrane potential in expanding Tcons with a concomitant reduction in basal autophagy. Our findings suggest that FOXP3 governs a distinct transcriptional program in early-stage effector Tcons that maintains RICD resistance via CD48-dependent protective autophagy and p53 suppression.

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Section: Foxp3 Knockdown Does Not Impact T-cell Proliferation or Sap mentioning

confidence: 89%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

FOXP3 protects conventional human T cells from premature restimulation-induced cell death

et al. 2019

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“…152 SAP has a tightly controlled expression profile, undetectable in HSC, B cells, T regs, or myeloid lineage cells, and levels change after T cell stimulation and within T cell subsets. [153][154][155] While toxicity has not been observed in murine models of gene therapy using a constitutive promoter, 156 concern remains that aberrant expression could lead to further dysregulation. Due to the most severe immune deficits arising due to lack of T cell function, a T cell gene therapy approach was pursued, which corrected many of the disease phenotypes in murine models.…”

Section: Gene Therapy For Primary Immune Deficiencies: Future Perspectivesmentioning

confidence: 99%

Gene therapy for primary immunodeficiency

Booth

Romano

Roncarolo

et al. 2019

Human Molecular Genetics

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Gene therapy is now being trialled as a therapeutic option for an expanding number of conditions, based primarily on the successful treatment over the past two decades of patients with specific primary immunodeficiencies (PIDs) including severe combined immunodeficiency and Wiskott–Aldrich syndrome and metabolic conditions such as leukodystrophy. The field has evolved from the use of gammaretroviral vectors to more sophisticated lentiviral platforms that offer an improved biosafety profile alongside greater efficiency for hematopoietic stem cells gene transfer. Here we review more recent developments including licensing of gene therapies, use of gene corrected autologous T cells as an alternative strategy for some PIDs and the potential of targeted gene correction using various gene editing platforms. Given the promising results of recent clinical trials, it is likely that autologous gene therapies will become standard of care for a number of devastating diseases in the coming decade.

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Characterization of Gene Expression Signatures for the Identification of Cellular Heterogeneity in the Developing Mammary Gland

Henry

Trousdell

Cyrill

et al. 2021

J Mammary Gland Biol Neoplasia

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The developing mammary gland depends on several transcription-dependent networks to define cellular identities and differentiation trajectories. Recent technological advancements that allow for single-cell profiling of gene expression have provided an initial picture into the epithelial cellular heterogeneity across the diverse stages of gland maturation. Still, a deeper dive into expanded molecular signatures would improve our understanding of the diversity of mammary epithelial and non-epithelial cellular populations across different tissue developmental stages, mouse strains and mammalian species. Here, we combined differential mammary gland fractionation approaches and transcriptional profiles obtained from FACS-isolated mammary cells to improve our definitions of mammary-resident, cellular identities at the single-cell level. Our approach yielded a series of expression signatures that illustrate the heterogeneity of mammary epithelial cells, specifically those of the luminal fate, and uncovered transcriptional changes to their lineage-defined, cellular states that are induced during gland development. Our analysis also provided molecular signatures that identified non-epithelial mammary cells, including adipocytes, fibroblasts and rare immune cells. Lastly, we extended our study to elucidate expression signatures of human, breast-resident cells, a strategy that allowed for the cross-species comparison of mammary epithelial identities. Collectively, our approach improved the existing signatures of normal mammary epithelial cells, as well as elucidated the diversity of non-epithelial cells in murine and human breast tissue. Our study provides a useful resource for future studies that use single-cell molecular profiling strategies to understand normal and malignant breast development.

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FOXP3 renders activated human regulatory T cells resistant to restimulation-induced cell death by suppressing SAP expression

Cited by 13 publications

References 48 publications

FOXP3 protects conventional human T cells from premature restimulation-induced cell death

FOXP3 protects conventional human T cells from premature restimulation-induced cell death

Gene therapy for primary immunodeficiency

Characterization of Gene Expression Signatures for the Identification of Cellular Heterogeneity in the Developing Mammary Gland

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