Identification of lineage-specifying cytokines that signal all CD8+-cytotoxic-lineage-fate 'decisions' in the thymus

Etzensperger, Ruth; Kadakia, Tejas; Tai, Xuguang; Alag, Amala; Guinter, Terry I.; Egawa, Takeshi; Erman, Batu; Singer, Alfred

doi:10.1038/ni.3847

Cited by 31 publications

(28 citation statements)

References 53 publications

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“…I-specific CD8 T cells only differentiate after a disruption of MHC class II/TCR signals and subsequent cytokine signaling. 84,85 Interestingly, in the presence of high levels of ectopic ZAP-70 from the AAV8-ZAP-70 vector (Fig 3, C), both the thymic and peripheral CD4/CD8 ratios in AAV8-ZAP-70-treated mice were significantly skewed to a CD4 lineage fate (P < .05; Figs 2, D, and 3, E).…”

Section: Intrathymic Aav8-zap-70 Transduction Promotes Long-term Mainmentioning

confidence: 92%

Intrathymic adeno-associated virus gene transfer rapidly restores thymic function and long-term persistence of gene-corrected T cells

Pouzolles

Machado

Guilbaud

et al. 2020

Journal of Allergy and Clinical Immunology

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Background: Patients with T-cell immunodeficiencies are generally treated with allogeneic hematopoietic stem cell transplantation, but alternatives are needed for patients without matched donors. An innovative intrathymic gene therapy approach that directly targets the thymus might improve outcomes. Objective: We sought to determine the efficacy of intrathymic adeno-associated virus (AAV) serotypes to transduce thymocyte subsets and correct the T-cell immunodeficiency in a zetaassociated protein of 70 kDa (ZAP-70)-deficient murine model. Methods: AAV serotypes were injected intrathymically into wild-type mice, and gene transfer efficiency was monitored. ZAP-70 2/2 mice were intrathymically injected with an AAV8 vector harboring the ZAP70 gene. Thymus structure, immunophenotyping, T-cell receptor clonotypes, T-cell function, immune responses to transgenes and autoantibodies, vector copy number, and integration were evaluated. Results: AAV8, AAV9, and AAV10 serotypes all transduced thymocyte subsets after in situ gene transfer, with transduction of up to 5% of cells. Intrathymic injection of an AAV8-ZAP-70 vector into ZAP-70 2/2 mice resulted in a rapid thymocyte differentiation associated with the development of a thymic medulla. Strikingly, medullary thymic epithelial cells expressing the autoimmune regulator were detected within 10 days of gene transfer, correlating with the presence of functional effector and regulatory T-cell subsets with diverse T-cell receptor clonotypes in the periphery. Although thymocyte reconstitution was transient, gene-corrected peripheral T cells harboring approximately 1 AAV genome per cell persisted for more than 40 weeks, and AAV vector integration was detected. Conclusions: Intrathymic AAV-transduced progenitors promote a rapid restoration of the thymic architecture, with a single wave of thymopoiesis generating long-term peripheral T-cell function.

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Section: Intrathymic Aav8-zap-70 Transduction Promotes Long-term Mainmentioning

confidence: 92%

Intrathymic adeno-associated virus gene transfer rapidly restores thymic function and long-term persistence of gene-corrected T cells

Pouzolles

Machado

Guilbaud

et al. 2020

Journal of Allergy and Clinical Immunology

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“…3C). IL-7 and TGF-b are two cytokines that are instrumental in phase 2 (31). Flow cytometry analyses revealed that 8M1 and 8M2 thymocytes from Psmb11 2/2 thymi had slightly but significantly lower levels of surface CD127 (Fig.…”

Section: Selection Of Cd8 Thymocytes Is Dysregulated In Psmb11 2/2 Thymimentioning

confidence: 97%

“…3C). In addition, a 3.5-fold downregulation in the expression of Itgae, which is specifically induced by TGF-b signaling (31), was observed in the 8SM subset from Psmb11 2/2 mice (Supplemental Table I). Overall, these data suggest that in Psmb11 2/2 thymi, CD8 thymocytes receive strong TCR signals but show evidence of impaired cytokine signaling thereafter.…”

Section: Selection Of Cd8 Thymocytes Is Dysregulated In Psmb11 2/2 Thymimentioning

confidence: 99%

PSMB11 Orchestrates the Development of CD4 and CD8 Thymocytes via Regulation of Gene Expression in Cortical Thymic Epithelial Cells

Apavaloaei

Brochu

Dong

et al. 2019

The Journal of Immunology

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T cell development depends on sequential interactions of thymocytes with cortical thymic epithelial cells (cTECs) and medullary thymic epithelial cells. PSMB11 is a catalytic proteasomal subunit present exclusively in cTECs. Because proteasomes regulate transcriptional activity, we asked whether PSMB11 might affect gene expression in cTECs. We report that PSMB11 regulates the expression of 850 cTEC genes that modulate lymphostromal interactions primarily via the WNT signaling pathway. cTECs from Psmb11−/− mice 1) acquire features of medullary thymic epithelial cells and 2) retain CD8 thymocytes in the thymic cortex, thereby impairing phase 2 of positive selection, 3) perturbing CD8 T cell development, and 4) causing dramatic oxidative stress leading to apoptosis of CD8 thymocytes. Deletion of Psmb11 also causes major oxidative stress in CD4 thymocytes. However, CD4 thymocytes do not undergo apoptosis because, unlike CD8 thymocytes, they upregulate expression of chaperones and inhibitors of apoptosis. We conclude that PSMB11 has pervasive effects on both CD4 and CD8 thymocytes via regulation of gene expression in cTECs.

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“…These findings indicate that iPSC-derived T cell differentiation may require the provision of additional physiologically relevant signals. Much has been learned over the past decades about how T cells develop within the thymus, and although the signals provided within the thymic microenvironment are still incompletely elucidated, they are not limited to Notch/Delta-like ligands and TCR stimulation as currently provided to iPSCs for in vitro differentiation (Etzensperger et al, 2017; Singer et al, 2008). …”

Section: Introductionmentioning

confidence: 99%

Generation of Tumor Antigen-Specific iPSC-Derived Thymic Emigrants Using a 3D Thymic Culture System

et al. 2018

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SUMMARY Induced pluripotent stem cell (iPSC)-derived T cells may provide future therapies for cancer patients, but those generated by current methods, such as the OP9/DLL1 system, have shown abnormalities that pose major barriers for clinical translation. Our data indicate that these iPSC-derived CD8 single-positive T cells are more like CD4+CD8+ double-positive T cells than mature naive T cells because they display phenotypic markers of developmental arrest and an innate-like phenotype after stimulation. We developed a 3D thymic culture system to avoid these aberrant developmental fates, generating a homogeneous subset of CD8ab+ antigen-specific T cells, designated iPSC-derived thymic emigrants (iTEs). iTEs exhibit phenotypic and functional similarities to naive T cells both in vitro and in vivo, including the capacity for expansion, memory formation, and tumor suppression. These data illustrate the limitations of current methods and provide a tool to develop the next generation of iPSC-based antigen-specific immunotherapies.

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Identification of lineage-specifying cytokines that signal all CD8+-cytotoxic-lineage-fate 'decisions' in the thymus

Cited by 31 publications

References 53 publications

Intrathymic adeno-associated virus gene transfer rapidly restores thymic function and long-term persistence of gene-corrected T cells

Intrathymic adeno-associated virus gene transfer rapidly restores thymic function and long-term persistence of gene-corrected T cells

PSMB11 Orchestrates the Development of CD4 and CD8 Thymocytes via Regulation of Gene Expression in Cortical Thymic Epithelial Cells

Generation of Tumor Antigen-Specific iPSC-Derived Thymic Emigrants Using a 3D Thymic Culture System

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