Publications
Publications
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Distinct type I and II interferon responses direct cortical and medullary thymic epithelial cell development.
Science immunology
2025; 10 (107): eado4720
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Abstract
Advances in genomics have redefined our understanding of thymic epithelial heterogeneity and architecture, yet signals driving thymic epithelial differentiation remain incompletely understood. Here, we elucidated pathways instructing human thymic epithelial cell development in the context of other anterior foregut-derived organs. Activation of interferon response gene regulatory networks distinguished epithelial cells of the thymus from those of other anterior foregut-derived organs. Thymic cortex and medulla epithelia displayed distinctive interferon-responsive signatures defined by lineage-specific chromatin accessibility. We explored the effects of type I and II interferons on thymic epithelial progenitor differentiation from induced pluripotent stem cells. Type II interferon was essential for expressing proteasome and antigen-presenting molecules, whereas type I or II interferons were essential for inducing different cytokines in thymic epithelial progenitor cells. Our findings suggest that interferons are critical to cortical and medullary thymic epithelial cell differentiation.
View details for DOI 10.1126/sciimmunol.ado4720
View details for PubMedID 40315299
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Clone tracking through repeated malaria identifies high-fidelity memory CD4 T cell responses.
Science immunology
2025; 10 (106): eads2957
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Abstract
Few studies have tracked human CD4+ T cell clones through repeated infections. We used longitudinal single-cell RNA and T cell receptor (TCR) tracking to study the functional stability and memory potential of CD4+ T cell clonotypes during repeated Plasmodium falciparum (Pf) infections in Ugandan children and adults. Nearly all clonotypes displayed a strong preference for one of seven CD4+ subsets. This phenomenon of "clonal fidelity" was influenced by clonal expansion, linking T cell polarization and proliferation in vivo. Using clone tracking, we characterized subset-specific activation trajectories and identified antigen-specific clones. Type 1 regulatory T (TR1) cells accounted for nearly 90% of Pf-specific CD4+ T cells in blood. Tracking these clones longitudinally for hundreds of days, we observed malaria-induced expansion of TR1 effectors, long-term persistence of TR1 memory cells, and high-fidelity recall responses after reinfection. This work establishes clonal fidelity as a natural phenomenon and demonstrates the stable, long-term memory potential of TR1 cells.
View details for DOI 10.1126/sciimmunol.ads2957
View details for PubMedID 40279404
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From promise to practice: CAR T and Treg cell therapies in autoimmunity and other immune-mediated diseases.
Frontiers in immunology
2024; 15: 1509956
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Abstract
Autoimmune diseases, characterized by the immune system's attack on the body's own tissues, affect millions of people worldwide. Current treatments, which primarily rely on broad immunosuppression and symptom management, are often associated with significant adverse effects and necessitate lifelong therapy. This review explores the next generation of therapies for immune-mediated diseases, including chimeric antigen receptor (CAR) T cell and regulatory T cell (Treg)-based approaches, which offer the prospect of targeted, durable disease remission. Notably, we highlight the emergence of CD19-targeted CAR T cell therapies, and their ability to drive sustained remission in B cell-mediated autoimmune diseases, suggesting a possible paradigm shift. Further, we discuss the therapeutic potential of Type 1 and FOXP3+ Treg and CAR-Treg cells, which aim to achieve localized immune modulation by targeting their activity to specific tissues or cell types, thereby minimizing the risk of generalized immunosuppression. By examining the latest advances in this rapidly evolving field, we underscore the potential of these innovative cell therapies to address the unmet need for long-term remission and potential tolerance induction in individuals with autoimmune and immune-mediated diseases.
View details for DOI 10.3389/fimmu.2024.1509956
View details for PubMedID 39697333
View details for PubMedCentralID PMC11653210
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Lentiviral-Mediated Gene Therapy for Patients with Fanconi Anemia [Group a]: Updated Results from Global RP-L102 Clinical Trials
ELSEVIER. 2024: 7463-7464
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View details for DOI 10.1182/blood-2024-194638
View details for Web of Science ID 001412753000027
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Transcriptional and epigenetic characterization of a new in vitro platform to model the formation of human pharyngeal endoderm.
Genome biology
2024; 25 (1): 211
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Abstract
The Pharyngeal Endoderm (PE) is an extremely relevant developmental tissue, serving as the progenitor for the esophagus, parathyroids, thyroids, lungs, and thymus. While several studies have highlighted the importance of PE cells, a detailed transcriptional and epigenetic characterization of this important developmental stage is still missing, especially in humans, due to technical and ethical constraints pertaining to its early formation.Here we fill this knowledge gap by developing an in vitro protocol for the derivation of PE-like cells from human Embryonic Stem Cells (hESCs) and by providing an integrated multi-omics characterization. Our PE-like cells robustly express PE markers and are transcriptionally homogenous and similar to in vivo mouse PE cells. In addition, we define their epigenetic landscape and dynamic changes in response to Retinoic Acid by combining ATAC-Seq and ChIP-Seq of histone modifications. The integration of multiple high-throughput datasets leads to the identification of new putative regulatory regions and to the inference of a Retinoic Acid-centered transcription factor network orchestrating the development of PE-like cells.By combining hESCs differentiation with computational genomics, our work reveals the epigenetic dynamics that occur during human PE differentiation, providing a solid resource and foundation for research focused on the development of PE derivatives and the modeling of their developmental defects in genetic syndromes.
View details for DOI 10.1186/s13059-024-03354-z
View details for PubMedID 39118163
View details for PubMedCentralID 5241818
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In Utero Hematopoietic Stem Cell Transplantation for Fanconi Anemia.
Blood advances
2024
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View details for DOI 10.1182/bloodadvances.2023011894
View details for PubMedID 38991119
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AML/T cell interactomics uncover correlates of patient outcomes and the key role of ICAM1 in T cell killing of AML.
Leukemia
2024
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Abstract
T cells are important for the control of acute myeloid leukemia (AML), a common and often deadly malignancy. We observed that some AML patient samples are resistant to killing by human-engineered cytotoxic CD4+ T cells. Single-cell RNA-seq of primary AML samples and CD4+ T cells before and after their interaction uncovered transcriptional programs that correlate with AML sensitivity or resistance to CD4+ T cell killing. Resistance-associated AML programs were enriched in AML patients with poor survival, and killing-resistant AML cells did not engage T cells in vitro. Killing-sensitive AML potently activated T cells before being killed, and upregulated ICAM1, a key component of the immune synapse with T cells. Without ICAM1, killing-sensitive AML became resistant to killing by primary ex vivo-isolated CD8+ T cells in vitro, and engineered CD4+ T cells in vitro and in vivo. While AML heterogeneity implies that multiple factors may determine their sensitivity to T cell killing, these data show that ICAM1 acts as an immune trigger, allowing T cell killing, and could play a role in AML patient survival in vivo.
View details for DOI 10.1038/s41375-024-02255-1
View details for PubMedID 38724673
View details for PubMedCentralID 6239928
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Molecular and functional identification of unstable regulatory and autoreactive effector T cells that are expanded in patients with FOXP3 mutation
ACADEMIC PRESS INC ELSEVIER SCIENCE. 2024
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View details for DOI 10.1016/j.clim.2024.110038
View details for Web of Science ID 001296205300102
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Lentiviral-Mediated Gene Therapy (RP-L102) for Fanconi Anemia [Group A], is Associated with Polyclonal Integration Patterns in the Absence of Conditioning
CELL PRESS. 2024: 132
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View details for Web of Science ID 001332783400246
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Gene Therapy for Adult and Pediatric Patients with Severe Pyruvate Kinase Deficiency: Results from a Global Study of RP-L301
CELL PRESS. 2024: 2-3
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View details for Web of Science ID 001332783400005