Biology subjects

Rica, R.

Publications and source records attributed to Rica, R..

6 recordsLinked to original sources

bioRxiv2025

Langerhans Cell-targeted mRNA Delivery: A Strategy for Dose-Sparing and Enhanced Anti-Tumor Immunity

Despite the success of mRNA therapeutics, challenges remain in optimizing immune responses and minimizing side effects. Cell-specific antigen delivery may help reduce required doses and improve vaccine efficacy. In this study, we report on the first targeted delivery system for mRNA to a specific subset of skin-resident antigen-presenting cells - Langerhans cells. By functionalizing lipid nanoparticles (LNPs) with a langerin-specific glycomimetic ligand, we achieve selective mRNA delivery to both murine and human primary Langerhans cells with minimal off-target uptake, at the same time resulting in significantly increased mRNA translation. This targeted mRNA delivery not only enhances antigen presentation and T cell responses but also enables dose-sparing and superior anti-tumor immunity compared to conventional immunization in a B16-OVA tumor model. Importantly, our platforms high compatibility with various lipid nanoparticle formulations offers a flexible and precise tool for skin-directed mRNA delivery.

immunology↗

bioRxiv2025

Langerhans Cell-targeted Protein Delivery Enhances Antigen-Specific Cellular Immune Response

Targeted antigen delivery to immune cells, particularly dendritic cells, has emerged as a promising strategy to enhance therapeutic efficacy of vaccines, while minimizing adverse effects associated with conventional immunization. In this study, we use our previously described small glycomimetic molecule that selectively recognizes the Langerhans cell (LC)-specific surface receptor Langerin and demonstrate specific delivery of protein antigens to these specialized dendritic cells. Our results show that Langerin-mediated antigen delivery significantly enhances the immune response in vivo, resulting in increased expansion and activation of antigen-specific T cells, compared to immunization with unmodified antigen. We demonstrate the feasibility of our LC-targeted platform for immune cell-specific immunization with protein antigen and underscore the potential of LCs as an access point for next-generation vaccines and immunotherapies.

immunology↗

bioRxiv2024

HDAC1 controls the generation and maintenance of effector-like CD8+ T cells during chronic viral infection

CD8+ T cell exhaustion is a complex process that involves the differentiation of persistently activated CD8+ T cells into functionally distinct cell subsets. Here, we investigated the role of the key epigenetic regulator histone deacetylase 1 (HDAC1) in the differentiation of exhausted T (Tex) cells during chronic viral infection. We uncovered that HDAC1 controls the generation and maintenance of effector-like CX3CR1+ Tex cells in a CD8+ T cell-intrinsic manner. Deletion of HDAC1 led to expansion of an alternative Tex cell subset characterized by high expression of T cell exhaustion markers, and this was accompanied by elevated viremia. HDAC1 knockout altered the chromatin landscape in progenitor Tex cells, abrogated the expression of effector-like signature genes and interfered with cell fate specification toward the CX3CR1+ Tex cell subset. We conclude that HDAC1 is functionally required for controlling viral load during chronic infection by ensuring adequate CX3CR1+ Tex cell subset differentiation. HighlightsO_LIHDAC1 promotes the generation of CX3CR1+ effector-like Tex cell subsets in chronic viral infection in a CD8+ T cell-intrinsic manner. C_LIO_LIDeletion of HDAC1 leads to an increase of a cell subset enriched in exhaustion markers and is accompanied with elevated viremia. C_LIO_LIHDAC1 is required for the maintenance of the CX3CR1+ Tex cell pool. C_LIO_LIHDAC1 deletion alters the chromatin landscape at effector-like signature gene loci in progenitor Tex cells. C_LI

immunology↗

bioRxiv2022

The guanine nucleotide exchange factor Rin-like acts as a gatekeeper for T follicular helper cell differentiation via regulating CD28 signaling

T follicular helper (Tfh) cells are essential for the development of germinal center B cells and high-affinity antibody producing B-cells in human and mice. Here, we identify the guanine nucleotide exchange factor (GEF) Rin-like (Rinl) as a negative regulator of Tfh generation. Loss of Rinl leads to an increase of Tfh in aging, upon in vivo immunization and acute LCMV Armstrong infection in mice, and in human CD4+ T cell in vitro cultures. Further, adoptive transfer experiments using WT and Rinl-KO naive CD4+ T cells unraveled T cell-intrinsic functions of Rinl. Mechanistically, Rinl regulates CD28 internalization and signaling, thereby shaping CD4+ T cell activation and differentiation. Thus, our results identify the GEF Rinl as a negative regulator of global Tfh differentiation in an immunological context and species-independent manner, and furthermore connect Rinl with CD28 internalization and signaling pathways in CD4+ T cells, demonstrating for the first-time the importance of endocytic processes for Tfh differentiation. HighlightsO_LIRinl-KO CD4+ T cells show increased Tfh differentiation in a context independent manner C_LIO_LIThe regulation of Tfh differentiation is T cell-intrinsic C_LIO_LIRinl controls CD28 endocytosis and shapes Tfh-specific CD28 signal transduction C_LIO_LIHuman Tfh differentiation is regulated by Rinl C_LI

immunology↗

bioRxiv2022

Nuclear receptor corepressor 1 controls regulatory T cell subset differentiation and effector function

FOXP3+ regulatory T cells (Treg cells) are key for immune homeostasis. Here, we reveal that nuclear receptor corepressor 1 (NCOR1) controls naive and effector Treg cell states. Upon NCOR1 deletion in T cells, effector Treg cell frequencies were elevated in mice and in in vitro-generated human Treg cells. NCOR1-deficient Treg cells failed to protect mice from severe weight loss and intestinal inflammation associated with CD4+ T cell transfer colitis, indicating impaired suppressive function. NCOR1 controls transcriptional integrity of Treg cells, since effector gene signatures were already upregulated in naive NCOR1-deficient Treg cells while effector NCOR1-deficient Treg cells failed to repress genes associated with naive Treg cells. Moreover, genes related to cholesterol homeostasis including targets of liver X receptor (LXR) were dysregulated in NCOR1-deficient Treg cells. However, genetic ablation of LXR{beta} in T cells did not revert the effects of NCOR1 deficiency, indicating that NCOR1 controls naive and effector Treg cell subset composition independent from its ability to repress LXR{beta}-induced gene expression. Thus, our study reveals that NCOR1 maintains naive and effector Treg cell states via regulating their transcriptional integrity. We also reveal a critical role for this epigenetic regulator in supporting the suppressive functions of Treg cells in vivo.

immunology↗

bioRxiv2022

24-Nor-ursodeoxycholic acid counteracts TH17/Treg imbalance and ameliorates intestinal inflammation by restricting glutaminolysis in differentiating TH17 cells

Objective24-Nor-ursodeoxycholic acid (NorUDCA) is a novel therapeutic bile acid for treating primary sclerosing cholangitis (PSC), an immune-mediated cholestatic liver disease. Since PSC strongly associates with inflammatory bowel diseases (IBD) driven by TH17/Treg imbalance, we aimed to explore NorUDCAs immunomodulatory potential on intestinal TH17/Treg balance. DesignNorUDCAs impact on TH17/Treg tissue distribution was first assessed in Mdr2-/- mouse model of PSC. We specifically investigated NorUDCAs effect on modulating TH17/Treg balance in a CD4+ T cell driven colitis model induced by adoptive transfer of CD25-CD44lowCD45RBhighCD4+ TNaive cells into Rag2-/- mice, mimicking human IBD. Mechanistic studies were performed using molecular approaches, flow cytometry and metabolic assays in murine TH17 cells in vitro. NorUDCAs signaling effects observed in murine system were further validated in circulating CD4+ T cells from PSC patients with co-existing IBD. ResultsNorUDCA promoted Treg generation in both liver and intestine in the Mdr2-/- model. In the experimental IBD model, NorUDCA attenuated intestinal immunopathology. Mechanistically, NorUDCA demonstrated strong immunomodulatory efficacy in counteracting TH17/Treg imbalance by restricting glutaminolysis in differentiating TH17 cells, thus suppressed -Ketoglutarate-dependent mTORC1 activation, glycolysis and enhanced FOXP3 expression. NorUDCAs impact on mTORC1 signaling was further confirmed in circulating CD4+ T-cells from PSC patients with IBD. ConclusionNorUDCA possesses direct immunometabolic modulatory potency to counteract TH17/Treg imbalance and ameliorate excessive TH17 cell driven intestinal immunopathology. These findings extend future clinical applications of NorUDCA for treatment of TH17 cell-mediated disorders along the gut-liver axis and beyond. Significance of this studyO_ST_ABSWhat is already known on this subject?C_ST_ABSO_LIPSC is an immune-mediated cholestatic liver disease highly associated with IBD where TH17/Treg imbalance drives immunopathogenesis; seeking effective therapeutics covering both liver and intestinal disease in PSC is of high clinical relevance. C_LIO_LIIndependent of anti-cholestatic effects, NorUDCA has recently been shown to possess direct immunomodulatory properties on CD8+ T cell metabolism, lymphoblastogenesis and clonal expansion through targeting mTORC1 signaling. C_LIO_LISince mTORC1 serves as critical metabolic checkpoint orchestrating TH17/Treg axis, inhibiting mTORC1 activity represents a potential treatment avenue counteracting TH17/Treg imbalance under intestinal inflammatory conditions. C_LI What are the new findings?O_LINorUDCA enriches FOXP3+ Treg population in both liver and intestinal tissue in the cholestatic Mdr2-/- mouse model of PSC. C_LIO_LINorUDCA exhibits direct immunomodulatory efficacies in suppressing excess TH17 cell-mediated intestinal immunopathology and promotes FOXP3+ Treg generation in an experimental IBD model. C_LIO_LIMechanistically, NorUDCA counteracts TH17/Treg imbalance by restricting glutaminolysis in differentiating TH17 cells, thus suppresses -Ketoglutarate-dependent mTORC1 activation, glycolysis and enhances FOXP3 expression. C_LIO_LINorUDCAs impact on mTORC1 signaling was further confirmed in circulating CD4+ T cells from patients with PSC and IBD. C_LI How might it impact on clinical practice in the foreseeable future?These findings advance our current understanding of therapeutic potentials of NorUDCA, which might represent a novel therapeutic strategy in the treatment of PSC and concomitant IBD and other TH17-mediated intestinal diseases.

molecular biology↗