Biology subjects

Maggi, J.

Publications and source records attributed to Maggi, J..

3 recordsLinked to original sources

bioRxiv2026

Specific killing of Ewing sarcoma by TCR-T cells targeting public neogene-encoded antigens

EWSR1::FLI1, the oncogenic chimeric transcription factor driving Ewing sarcoma (EwS)induces expression of exquisitely EwS-specific neogenes (Ew_NGs) through neomorphic binding and transcription activation at GGAA microsatellites in genomic regions that are silent in normal tissues. We show that peptides encoded by Ew_NGs are presented on HLA-I complexes on EwS cells. The cytokine secretion of CD8+ T cells specific for Ew_NG-encoded HLA-I-bound peptides is activated by all HLA-I-matched EwS cells but not by non-EwS cells. These T cells kill EwS cells in an HLA-I restricted manner. This cytotoxicity is dependent on the expression of EWSR1::FLI1 and of the corresponding Ew_NG. It can be reproduced by transduction of the TCR into donor T cells (TCR-T) which kill EwS cells in vivo. Moreover, we show that neither off target nor allogeneic activation are observed with TCR-T thus paving the way for cell therapy in relapsed/resistant EwS patients for which therapeutic options are very limited. Statement of significanceThe chimeric transcription factor EWSR1::FLI1 generates tumor-specific neogenes encoding neoantigen presented by the HLA-I molecules of Ewing cells. Neoantigen-specific CD8+ T-cell clones and engineered TCR-T cells can selectively recognize and kill EwS tumor cells in vitro and in vivo.

immunology↗

bioRxiv2025

Major histocompatibility complex class II-expressing bone marrow megakaryocytes activate CD4+ T cells and induce regulatory T cell fate

While professional antigen-presenting cells drive adaptive immunity, atypical cell types can fulfill this role in the bone marrow. Megakaryocytes (MKs) are canonically recognized for platelet production, but recent studies indicate functional heterogeneity and immune potential. We found that ~20% of bone marrow MKs express Major Histocompatibility Complex (MHC) II and co-stimulatory receptors CD80, CD86, CD40, and CD83. These MKs process and present antigen to activate T cells ex vivo in an MHC II-dependent manner. MK/T cell interactions induced TGF-{beta}1 secretion and promoted induced Treg differentiation. Prior stimulation of MKs with LPS or Poly I:C was associated with modest Th1-associated CD4+ T cell responses, including IFN-{gamma} and TNF- production, without robust Th17 differentiation. Immunopeptidomics of the murine MK MHC II receptor confirmed occupancy by exogenous peptides, suggesting in vivo functionality. Using a murine model with MK-targeted deletion of MHC II (Pf4-MHC{Delta}/{Delta}), we observed altered TLR signaling and reduced bone marrow TGF-{beta}1. Together, these findings identify MHC II+ MKs as noncanonical antigen-presenting cells with the potential to modulate CD4 T cell responses as part of the immune regulation of the bone marrow niche.

immunology↗

bioRxiv2024

Putative Role of Norrin in Neuroretinal Differentiation Revealed by bulk and scRNA Sequencing of Human Retinal Organoids

Pathogenic variants in the X-linked gene NDP (Norrie disease protein) have been associated with a variety of non-syndromic and syndromic human retinal diseases, including Norrie disease and familial exudative vitroretinopathy. The gene codes for Norrin, a secreted angiogenic molecule which binds to FZD4 and its co-receptors LRP5/6 and TSPAN12 and activates Wnt-signaling. Additionally, it also potentiates Wnt-signaling by binding to the LGR4 receptor. Norrin was also found to exert a neuroprotective function in the retina, specifically for retinal ganglion cells. Furthermore, it was suggested to be involved in neurodevelopmental processes such as early neuro-ectodermal specification and differentiation, as well as maintenance of cochlear hair cells. To better understand the putative role of Norrin in neuronal cells of the retina we generated NDP mutant and eGFP-expressing NDP reporter human induced pluripotent stem cells, which were differentiated to retinal organoids. Bulk RNA sequencing and fixed single-cell RNA sequencing revealed alterations in gene expression as well as cellular composition, with increased proportions of retinal progenitors as well as Muller glia cells in NDPKO retinal organoids. Differential expression of genes related to glutamate signaling, Wnt and MAPK signaling, as well as neurogenesis was detected. Furthermore, genes associated with functions in the extracellular matrix were also differentially expressed. The considerable decrease in retinal neurons found in our NDPKO organoids suggest that Norrin is also important for retinal neurogenesis, which may precede the vascular manifestations in NDP-associated diseases.

neuroscience↗