Stem-Cell-Derived β-Like Cells with a Functional PTPN2 Knockout Display Increased Immunogenicity

Area of Science:

• Immunology
• Genetics
• Endocrinology

Background:

• Type 1 diabetes is a polygenic autoimmune disease targeting insulin-producing beta cells.
• The PTPN2 gene is a known risk factor for type 1 diabetes, but its precise role remains unclear.
• Understanding gene function in beta cells is crucial for elucidating autoimmune diabetes development.

Purpose of the Study:

• To investigate the functional role of PTPN2 in human beta cells.
• To determine how PTPN2 deficiency affects beta cell immune recognition and autoimmune responses.

Main Methods:

• CRISPR/Cas9 gene editing to create PTPN2 knockout human pluripotent stem cells.
• Differentiation of stem cells into stem-cell-derived beta-like cells (sBC).
• Transcriptomic and protein analyses, including HLA Class I expression and co-culture with T cells.

Main Results:

• PTPN2 knockout did not affect sBC differentiation efficiency.
• PTPN2 knockout sBC showed increased HLA Class I expression, especially under inflammatory conditions.
• PTPN2 knockout sBC exhibited enhanced immune stimulation of autoreactive T cells.

Conclusions:

• Dysregulated PTPN2 expression in human beta cells may increase their susceptibility to immune attack.
• PTPN2 deficiency could prime autoimmune T cell reactivity, contributing to type 1 diabetes.
• These findings highlight PTPN2's potential role in the autoimmune destruction of beta cells.