Hide and Seek- Protecting Human β-cells in T1D by modulating their PDL1 and HLA Class I expression

The β-cells in T1D

Background: In type 1 diabetes (T1D), β-cells co-orchestrate their own demise by increasing their visibility to the immune system. The balance between HLA Class I and PDL1 expression is critical: β-cells in T1D overexpress HLA Class I, which increases antigen presentation, but also overexpress PDL1, which offers partial immune protection. Identification of novel strategies to dissociate these two opposing mechanisms could be key in the development of novel T1D treatments.

Aims: We aim to validate suggested (e.g., STAT2) and novel targets for HLA Class I and PDL1 dissociation in standardized human islet-immune injury models and to increase the throughput of these models and endpoints to enable the discovery of new T1D therapeutics.

Methods: To enable high-throughput-compatible studies of these mechanisms in vitro, we established three islet-immune injury models by culturing spheroids derived from primary human islets (hIsMTs) with proinflammatory cytokines, activated peripheral blood mononuclear cells or HLA-A2-restricted preproinsulin-specific cytotoxic T lymphocytes. We are using these models to modulate gene expression of putative targets and investigate effects on PDL1 and HLA Class I expression, β-cell function and survival, and T-cell infiltration.

Results: In these models, β-cell impairment manifested as increased basal and decreased glucose-stimulated insulin release, decreased intracellular insulin content, loss of the first-phase insulin response, increased proinsulin-to-insulin ratios, and inflammatory chemokine release. Liraglutide and HLA Class I blocking antibodies demonstrated anti-inflammatory and immune-protective effects and were established as positive controls. Culturing hIsMTs with TNF-α + IL-1β + IFN-γ upregulated both HLA class I and PDL1 in hIsMTs, as determined by transcriptomic analysis and 3D confocal microscopy. The next steps will focus on investigating the effects of TYK2-inhibitors and STAT2 knockdown on β-cell survival and function in the established human islet-PPI CTL co-culture.

Conclusions: The described biomimetic human islet-immune assays represent valuable in vitro models for the long-term, high-throughput and precise study of early-stage T1D immunopathology and β-cell dysfunction. Our data confirm the anti-inflammatory effects of GLP-1RAs and successful immune evasion by HLA Class I interference, supporting the importance of both strategies for protecting β-cells from the immune-mediated attack that leads to T1D.

Download InSphero's comprehensive poster about human β-cells in T1D

Scroll to Top

Your Success is Our Mission - Get in Touch

Fill in form below to contact our 3D in vitro experts

Sign up for our Newsletter

Get the latest news on 3D in vitro research

View resource

Fill in the form below to view this resource