Biology subjects

Barra, J. M.

Publications and source records attributed to Barra, J. M..

5 recordsLinked to original sources

bioRxiv2026

Beta cell reactivity defines disease-relevant pancreatic CD8 T cells in type 1 diabetes

Type 1 diabetes (T1D) is characterized by immune-mediated destruction of pancreatic beta cells, yet the properties that distinguish disease-associated CD8 T cells from other pancreatic resident T cells remain incompletely defined. In this study, we analyzed CD8 T cell receptor (TCR) clonotypes isolated from the pancreas of organ donors with and without T1D and assessed their reactivity to beta cells using stem cell-derived beta-like cells. We found that highly beta cell-reactive CD8 T cells were selectively present in the pancreas of T1D donors but were largely absent from donors without T1D. In contrast, virus-specific CD8 T cells were detected in pancreata of donors with and without T1D and showed no evidence of cross-reactivity to beta-like cells, indicating that pancreatic residency alone does not confer beta cell specificity. Among beta cell-reactive CD8 T cells in T1D, reactivity to native peptides from major islet proteins other than preproinsulin was rare. Thus, despite beta cell specificity as a hallmark of T1D, T cells reactive to native islet proteins other than preproinsulin do not infiltrate the islets. These results identify beta cell reactivity as a key functional feature separating T1D-associated CD8 T cells from other pancreatic T cells. This functional definition of pathogenic T cells offers a framework for understanding selective beta cell loss and for developing approaches to monitor and therapeutically target disease-relevant CD8 T cells.

immunology↗

bioRxiv2025

Anti-CD3 microporous annealed particle hydrogel protects stem cell derived beta cells from autoreactive T cells

Type 1 diabetes (T1D) results from autoimmune destruction of pancreatic beta cells, leaving patients dependent on exogenous insulin and at risk of severe hypoglycemic episodes. Stem cell-derived beta-like cells (sBCs) offer a promising approach for beta cell replacement therapy, but clinical translation is limited by immune-mediated rejection, recurrent autoimmunity, and inhospitable transplantation sites. Biomaterials have been investigated to provide localized immune-isolation and immunomodulation, but foreign body responses and rapid depletion of therapeutic agents remain as obstacles to clinical translation. Here, we present a microporous annealed particle (MAP) hydrogel functionalized with an anti-CD3 monoclonal antibody (CD3) to provide a localized immunomodulatory microenvironment for beta cell replacement therapy. MAP hydrogels consisting of guest-host interlinked polyethylene glycol-maleimide (PEG-MAL) microgels supported rapid vascularization, minimal foreign body response, and engraftment of syngeneic islets in mice. CD3 MAP hydrogel halted T cell migration in vitro and protected transplanted sBCs from immune-mediated destruction by HLA-matched diabetogenic T cells in vivo. Subcutaneous CD3 functionalized MAP hydrogel also protected the endogenous islets in the pancreas, demonstrating potential for systemic immune modulation. These findings establish CD3 MAP hydrogels as a promising strategy for localized immune modulation in cell replacement therapy.

bioengineering↗

bioRxiv2025

Inhibition of cell-mediated immunity in type 1 diabetes by beta cell-targeted PD-1 agonists in pancreas tissue slices

Tissue-targeted immunotherapies for type 1 diabetes (T1D) hold potential to protect pancreatic beta cells while minimizing systemic immunosuppression. We used a bispecific agonist called Immune Modulating Monoclonal-TCR Against Autoimmune Disease (ImmTAAI), consisting of a T cell receptor (TCR) targeting domain fused with a PD-1 agonist to specifically bind beta cells and suppress autoreactive T cells. We used live pancreas slices to demonstrate targeting of ImmTAAI molecules to pre-proinsulin peptide-HLA-A2 complexes on human beta cells. ImmTAAI protected beta cells from T cell killing by increasing T cell motility and inhibiting cytokine secretion. ImmTAAI treatment also increased the motility of islet-infiltrating T cells in slices from a donor with recent-onset T1D and preserved insulin secretion in slices co-cultured with T cell avatars transduced with diabetogenic TCRs. These data demonstrate that ImmTAAI molecules have the potential to limit T cell activity locally, making this an attractive platform to elicit targeted immunoregulation in T1D. One Sentence SummaryWe demonstrate inhibition of cellular immunity in human type 1 diabetes using a beta cell-targeting, affinity-enhanced TCR fused to a PD-1 agonist.

bioengineering↗

bioRxiv2025

Human Stem Cell-Derived β-cells Expressing An Optimized CD155 Reduce Cytotoxic Immune Cell Function for Application in Type 1 Diabetes

Insulin-producing {beta}-cell replacement therapies offers a potential treatment for type 1 diabetes (T1D) but faces challenges from donor shortages and immune rejection. Stem cell-derived {beta}-cells (sBC) provide a renewable source but remain vulnerable to immune attack. We engineered human pluripotent stem cells to express either the wildtype (WT) or a high-affinity mutant (Mut) variant (rs1058402, G>A; Ala67Thr) of the NK and T cell checkpoint inhibitor CD155 before differentiation into sBC. Modified sBC maintained upregulated CD155 expression and showed enhanced binding to co-receptor ligands. Co-culture studies revealed that CD155 Mut-expressing sBC suppressed CD8+ T cell and NK cell activation and proliferation by preferentially engaging the co-inhibitory receptor TIGIT. Both CD155 Mut sBC lines reduced autoreactive CD8+ T cell- and NK cell-mediated sBC destruction and cytotoxic molecule secretion. This protection was lost with TIGIT blockade, confirming the role of CD155-TIGIT signaling in antagonizing immune cell-mediated killing. Our findings suggest that high-affinity CD155 expression enhances immune evasion of sBC, improving their potential for restorative therapy in T1D. TeaserEngineered {beta}-cells with a mutant CD155 help evade immune attack, offering a promising therapeutic approach for type 1 diabetes.

immunology↗

bioRxiv2024

Peptide Coated Polycaprolactone-Benzalkonium Chloride Nanocapsules for Targeted Drug Delivery to the Pancreatic β-Cell

Targeting of current therapies to treat or prevent loss of pancreatic islet {beta}-cells in Type 1 Diabetes (T1D) may provide improved efficacy and reduce off target effects. Current efforts to target the {beta}-cell are limited by a lack of {beta}-cell specific targets and the inability to test multiple targeting moieties with the same delivery vehicle. Here we fabricate a novel tailorable polycaprolactone nanocapsule (NC) where multiple different targeting peptides can be interchangeably attached for {beta}-cell specific delivery. Incorporation of a cationic surfactant in the NC shell allows for the attachment of Exendin-4 and an antibody for ectonucleoside triphosphate diphosphohydrolase 3 (ENTPD3) for {beta}-cell specific targeting. The average NC size ranges from 250-300nm with a polydispersity index under 0.2. The NCs are non-toxic, stable in media culture, and can be lyophilized and reconstituted. NCs coated with targeting peptide were taken up by human cadaveric islet {beta}-cells and human stem cell-derived {beta}-like cells (sBC) in vitro with a high level of specificity. Furthermore, NCs successfully delivered both hydrophobic and hydrophilic cargo to human {beta}-cells. Finally, Exendin-4 coated NCs were stable and targeted the mouse pancreatic islet {beta}-cell in vivo. Our unique NC design allows for the interchangeable coating of targeting peptides for future screening of targets with improved cell specificity. The ability to target and deliver thera-peutics to human pancreatic {beta}-cells opens avenues for improved therapies and treatments to help the delay onset, prevent, or reverse T1D.

bioengineering↗