在 1 型糖尿病 (T1D) 的进展过程中，β 细胞面临巨大的压力，因此需要适应性反应才能生存。面对自身免疫，能够保持 β 细胞功能和存活的适应性机制仍不清楚。在这里，我们发现，在出现胰岛素炎之前，非肥胖糖尿病 (NOD) 小鼠 β 细胞中未折叠蛋白反应 (UPR) 基因 Atf6α 或 Ire1α 的缺失会产生 p21 驱动的早期衰老表型，并显着改变 β 细胞分泌组。增强白血病抑制因子介导的 M2 巨噬细胞向胰岛的募集。因此，M2 巨噬细胞促进抗炎反应和免疫监视，从而消除胰岛炎症、去除终末衰老的 β 细胞、减少 β 细胞凋亡并预防 T1D。我们进一步证明 p21 介导的早期衰老特征在 T1D 患者的残余 β 细胞中是保守的。我们的研究结果揭示了 β 细胞 UPR 与衰老之间以前未被认识的联系，如果加以利用，可能代表一种新的 T1D 预防策略。版权所有 © 2023 作者。由爱思唯尔公司出版。保留所有权利。

During the progression of type 1 diabetes (T1D), β cells are exposed to significant stress and, therefore, require adaptive responses to survive. The adaptive mechanisms that can preserve β cell function and survival in the face of autoimmunity remain unclear. Here, we show that the deletion of the unfolded protein response (UPR) genes Atf6α or Ire1α in β cells of non-obese diabetic (NOD) mice prior to insulitis generates a p21-driven early senescence phenotype and alters the β cell secretome that significantly enhances the leukemia inhibitory factor-mediated recruitment of M2 macrophages to islets. Consequently, M2 macrophages promote anti-inflammatory responses and immune surveillance that cause the resolution of islet inflammation, the removal of terminally senesced β cells, the reduction of β cell apoptosis, and protection against T1D. We further demonstrate that the p21-mediated early senescence signature is conserved in the residual β cells of T1D patients. Our findings reveal a previously unrecognized link between β cell UPR and senescence that, if leveraged, may represent a novel preventive strategy for T1D.Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.