<b>Killing of human beta cells by CD8</b>^{<strong>+</strong>}<b> T-cells triggers inflammatory paracrine signaling and neighboring beta cell dysfunction</b>

<p dir="ltr">Type 1 diabetes is a progressive autoimmune disease characterized by the selective destruction of insulin-producing beta cells by CD8⁺ T-cells. Although the mechanisms of antigen-specific beta cell killing are well established, the broader consequences of this targeted destruction on neighboring beta cells that escape direct TCR-mediated attack, remain poorly understood. Here, we developed a co-culture model of HLA-A2-expressing human beta cells cultured as pseudo-islets and CD8⁺ T-cells specific for the INS_15-24 epitope. Using this new <i>in vitro</i> model, we demonstrate that (i) beta cell death induced by CD8⁺ T-cells strictly depends on TCR-HLA class I interactions; (ii) neighboring beta cells that evade direct T-cell contact do not alter beta cell identity or glucose-stimulated insulin secretion. However, they exhibit increased expression of inflammatory markers, reduced insulin content and impaired protein translation. The robust, versatile and readily applicable model described here represents a strong basis to further address paracrine signaling that extend beyond direct cytotoxicity.</p>