heterotopic-hindlimb-to-neck-transplantation-mouse-supermicrosurgical

Heterotopic Hindlimb-to-Neck Transplantation in the Mouse: A Supermicrosurgical Model of Vascularized Composite Allotransplantation

Vascularized composite allotransplantation (VCA) is increasingly recognized as a reconstructive option that offers substantial benefits for patients with ...

New York University Grossman School of Medicine

Hidradenitis suppurativa (HS) is a chronic, debilitating inflammatory skin disease characterized by keratinized epithelial tunnels that grow deeply into the dermis. Here, we examined the immune microenvironment within human HS lesions. Multi-omics profiling and multiplexed imaging identified tertiary lymphoid structures (TLSs) near HS tunnels. These TLSs were enriched with proliferative T cells, including follicular helper (Tfh), regulatory (Treg), and pathogenic T cells (IL17A+ and IFNG+), alongside extensive clonal expansion of plasma cells producing antibodies reactive to keratinocytes. HS fibroblasts express CXCL13 or CCL19 in response to immune cytokines. Using a microfluidic system to mimic TLS on a chip, we found that HS fibroblasts critically orchestrated lymphocyte aggregation via tumor necrosis factor alpha (TNF-α)-CXCL13 and TNF-α-CCL19 feedback loops with B and T cells, respectively; early TNF-α blockade suppressed aggregate initiation. Our findings provide insights into TLS formation in the skin, suggest therapeutic avenues for HS, and reveal mechanisms that may apply to other autoimmune settings, including Crohn's disease.

Skin immune-mesenchymal interplay within tertiary lymphoid structures promotes autoimmune pathogenesis in hidradenitis suppurativa.

Embryonic development in many species, including case reports in humans, can be temporarily halted before implantation during a process called diapause. Facultative diapause occurs under conditions of maternal metabolic stress such as nursing. While molecular mechanisms of diapause have been studied, a natural inducing factor has yet to be identified. Here, we show that oxytocin induces embryonic diapause in mice. We show that gestational delays were triggered during nursing or optogenetic stimulation of oxytocin neurons simulating nursing patterns. Mouse blastocysts express oxytocin receptors, and oxytocin induced delayed implantation-like dispersion in cultured embryos. Last, oxytocin receptor-knockout embryos transferred into wild-type surrogates had low survival rates during diapause. Our results indicate that oxytocin coordinates timing of embryonic development with uterine progression through pregnancy, providing an evolutionarily conserved mechanism for ensuring successful reproduction.

Oxytocin induces embryonic diapause.

Decoding Tertiary Lymphoid Structures in Hidradenitis Suppurativa: New Mechanistic Insights.

Expression of Glandular Genes in the Tunnel Epithelium of Hidradenitis Suppurativa.

The capability to profile the landscape of antigen-binding affinities of a vast number of antibodies (B cell receptors, BCRs) will provide a powerful tool to reveal biological insights. However, experimental approaches for detecting antibody-antigen interactions are costly and time-consuming and can only achieve low-to-mid throughput. In this work, we developed Cmai (contrastive modeling for antigen-antibody interactions) to address the prediction of binding between antibodies and antigens that can be scaled to high-throughput sequencing data. We devised a biomarker based on the output from Cmai to map the antigen-binding affinities of BCR repertoires. We found that the abundance of tumor antigen-targeting antibodies is predictive of immune-checkpoint inhibitor (ICI) treatment response. We also found that, during immune-related adverse events (irAEs) caused by ICI, humoral immunity is preferentially responsive to intracellular antigens from the organs affected by the irAEs. We used Cmai to construct a BCR-based irAE risk score, which predicted the timing of the occurrence of irAEs.

Profiling antigen-binding affinity of B cell repertoires in tumors by deep learning predicts immune-checkpoint inhibitor treatment outcomes.

Therapeutically targeting pathogenic T cells in autoimmune diseases has been challenging. Although LAG-3, an inhibitory checkpoint receptor specifically expressed on activated T cells, is known to bind to major histocompatibility complex class II (MHC class II), we demonstrate that MHC class II interaction alone is insufficient for optimal LAG-3 function. Instead, LAG-3's spatial proximity to T cell receptor (TCR) but not CD4 co-receptor, facilitated by cognate peptide-MHC class II, is crucial in mediating CD4 T cell suppression. Mechanistically, LAG-3 forms condensate with TCR signaling component CD3ε through its intracellular FSAL motif, disrupting CD3ε/lymphocyte-specific protein kinase (Lck) association. To exploit LAG-3's proximity to TCR and maximize LAG-3-dependent T cell suppression, we develop an Fc-attenuated LAG-3/TCR inhibitory bispecific antibody to bypass the requirement of cognate peptide-MHC class II. This approach allows for potent suppression of both CD4 and CD8 T cells and effectively alleviates autoimmune symptoms in mouse models. Our findings reveal an intricate and conditional checkpoint modulatory mechanism and highlight targeting of LAG-3/TCR cis-proximity for T cell-driven autoimmune diseases lacking effective and well-tolerated immunotherapies.

Article	Year
Skin immune-mesenchymal interplay within tertiary lymphoid structures promotes autoimmune pathogenesis in hidradenitis suppurativa. Immunity\| PubMed ID: 39662091	2024
Oxytocin induces embryonic diapause. Science advances\| PubMed ID: 40043121	2025
Decoding Tertiary Lymphoid Structures in Hidradenitis Suppurativa: New Mechanistic Insights. The Journal of investigative dermatology\| PubMed ID: 40152835	2025
Expression of Glandular Genes in the Tunnel Epithelium of Hidradenitis Suppurativa. The Journal of investigative dermatology\| PubMed ID: 40158768	2025
Profiling antigen-binding affinity of B cell repertoires in tumors by deep learning predicts immune-checkpoint inhibitor treatment outcomes. Nature cancer\| PubMed ID: 40579590	2025
Proximity between LAG-3 and the T cell receptor guides suppression of T cell activation and autoimmunity. Cell\| PubMed ID: 40592325	2025

Catherine Pei-Ju Lu

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