Biology subjects

Alegre, M.-L.

Publications and source records attributed to Alegre, M.-L..

4 recordsLinked to original sources

bioRxiv2026

immgenT: A Comprehensive Reference of Convergent T-cell States in the Mouse

The immgenT collaborative project generated a comprehensive molecular atlas of T cells spanning virtually all mouse organs and disease states, profiling ~800,000 cells from 750 samples with RNA, 128-plex surface protein, and {beta}TCR sequence. Applying a deep generative model to joint RNA and protein data defined the landscape of T-cell states organized into eight lineages and 107 robust clusters, integrating similar cells from different contexts, and resolving prior nomenclatures. Analysis of effector molecules, transcription factors and modules showed that both immunological functions and regulatory programs are shared across cell states. This framework provides a stable, reusable reference, demonstrated by computationally integrating 16 external datasets from diverse biological contexts. A set of public web tools supports browsing of these data and mapping of any dataset onto the immgenT framework. These results propose a molecular classification of T cells organized around a set of shared states reused across immunological contexts.

immunology↗

bioRxiv2025

Comparative ScRNA-Seq Profiling of Antigen-Specific CD4+ T cells in Semi-Allogeneic Transplantation and Pregnancy Reveals Intersecting Signatures of Rejection and Tolerance

Transplantation of allogeneic organs requires lifelong immunosuppression to prevent rejection. Prior sensitization and resultant memory T cells are barriers to achieving successful transplant tolerance. In reproductive immunology by contrast, pregnancy represents a spontaneous model of tolerance where the semi-allogeneic fetus evades rejection even in multiparous or rejection-sensitized mothers. CD8+ T cell phenotypes of tolerance and rejection have been previously reported in transplant and pregnancy, but the transcriptional states of donor and fetus-specific CD4+ T cells remain poorly defined. Here, we performed Single-cell RNA-sequencing on endogenous, antigen-specific CD4+ T cells across models of allogeneic heart transplants and naive or paternal skin-sensitized pregnancy. We identified expanded T follicular helper (Tfh) and non-follicular effectors in transplant rejection absent in tolerance. Naive pregnancy resulted in a modest expansion of effector clusters with transcriptional quiescence that mirrored virgin mice. Successful sensitized pregnancy resulted in expanded Tfh clusters consistent with increased fetal-specific antibodies and limited non-Tfh effector responses. Most striking were the extensive changes imposed on donor-specific Foxp3pos regulatory T cells (Tregs) resulting in the co-clustering together with Foxp3neg T conventional cells (Tconvs) in transplant tolerance and the emergence of a Foxp3neg Type I Regulatory cluster observed in pregnancy of sensitized dams. Finally, we showed that these transcriptomes were relevant and enriched in human datasets of health and disease respectively. Thus, the context-dependent signatures of antigen-specific CD4+ T cells provide new insights into their divergent responses to allogeneic conflict at the intersection of transplant and reproductive immunology. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=178 HEIGHT=200 SRC="FIGDIR/small/663404v2_ufig1.gif" ALT="Figure 1"> View larger version (55K): org.highwire.dtl.DTLVardef@1b30a86org.highwire.dtl.DTLVardef@17820cforg.highwire.dtl.DTLVardef@1b1fbeaorg.highwire.dtl.DTLVardef@11ff17_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2024

Efficacy and limitations of combined A2.CAR Treg and anti-CD154 therapy in a mouse model of haplo-mismatched heart transplantation

Successful allograft specific tolerance induction would eliminate the need for daily immunosuppression and improve post-transplant quality of life. Adoptive cell therapy with regulatory T cells expressing donor-specific Chimeric Antigen Receptors (CAR-Tregs) is a promising strategy, but as monotherapy, cannot prolong the survival with allografts with multiple MHC mismatches. Using an HLA-A2-transgenic haplo-mismatched heart transplantation model in immunocompetent C57Bl/6 recipients, we show that HLA-A2-specific (A2) CAR Tregs was able to synergize with low dose of anti-CD154 to enhance graft survival. Using haplo-mismatched grafts expressing the 2W-OVA transgene and tetramer-based tracking of 2W- and OVA-specific T cells, we showed that in mice with accepted grafts, A2.CAR Tregs inhibited endogenous non-A2 donor- specific T cell, B cell and antibody responses, and promoted a significant increase in endogenous FoxP3+Tregs with indirect donor-specificity. By contrast, in mice where A2.CAR Tregs failed to prolong graft survival, FoxP3neg A2.CAR T cells preferentially accumulated in rejecting allografts and endogenous donor-specific responses were not controlled. This study therefore provides the first evidence for synergy between A2.CAR Tregs and CD154 blockade to promote infectious tolerance in immunocompetent recipients of haplo-mismatched heart grafts and defines features of A2.CAR Tregs when they fail to reshape host immunity towards allograft tolerance.

immunology↗

bioRxiv2021

Restored TDCA and Valine Levels Imitate the Effects of Bariatric Surgery

Obesity is widespread and linked to various co-morbidities. Bariatric surgery has been identified as the only effective treatment, promoting sustained weight loss and the remission of co-morbidities. We performed sleeve-gastrectomies (SGx) in a pre-clinical mouse model of diet-induced obesity (DIO), delineating the effects on long-term remission from obesity. SGx resulted in sustained weight loss and improved glucose tolerance. Mass-spectrometric metabolomic profiling revealed significantly reduced systemic levels of taurodeoxycholic acid (TDCA) and L-valine in DIO mice. Notably, TDCA and L-Valine levels were restored after SGx in both human and mice to levels comparable with lean controls. Strikingly, combined systemic treatment with TDCA and valine induced a profound weight loss in DIO mice analogous to effects observed after SGx. Utilizing indirect calorimetry, we confirmed reduced food intake as causal for TDCA/valine-mediated weight loss via a central inhibition of the melanin-concentrating hormone. In summary, we identified restored TDCA/valine levels as an underlying mechanism of SGx-derived effects on weight loss. Of translational relevance, TDCA and L-valine are presented as novel agents promoting weight loss while reversing obesity-associated metabolic disorders.

cell biology↗