TY - JOUR
T1 - Towards antigen-specific Tregs for type 1 diabetes
T2 - Construction and functional assessment of pancreatic endocrine marker, HPi2-based chimeric antigen receptor
AU - Radichev, Ilian A.
AU - Yoon, Jeongheon
AU - Scott, David W.
AU - Griffin, Kurt
AU - Savinov, Alexei Y.
N1 - Publisher Copyright:
© 2020 Elsevier Inc.
PY - 2020/12
Y1 - 2020/12
N2 - Type 1 Diabetes (T1D) is an autoimmune disease marked by direct elimination of insulin-producing β cells by autoreactive T effectors. Recent T1D clinical trials utilizing autologous Tregs transfers to restore immune balance and improve disease has prompted us to design a novel Tregs-based antigen-specific T1D immunotherapy. We engineered a Chimeric Antigen Receptor (CAR) expressing a single-chain Fv recognizing the human pancreatic endocrine marker, HPi2. Human T cells, transduced with the resultant HPi2-CAR, proliferated and amplified Granzyme B accumulation when co-cultured with human, but not mouse β cells. Furthermore, following exposure of HPi2-CAR transduced cells to islets, CD8+ lymphocytes demonstrated enhanced CD107a (LAMP-1) expression, while CD4+ cells produced increased levels of IL-2. HPi2-CAR Tregs failed to maintain expansion due to a persistent tonic signaling from the CAR engagement to unexpectantly HPi2 antigen present on Tregs. Overall, we show lack of functionality of HPi2-CAR and highlight the importance of careful selection of CAR recognition driver for the sustainable activity and expandability of engineered T cells.
AB - Type 1 Diabetes (T1D) is an autoimmune disease marked by direct elimination of insulin-producing β cells by autoreactive T effectors. Recent T1D clinical trials utilizing autologous Tregs transfers to restore immune balance and improve disease has prompted us to design a novel Tregs-based antigen-specific T1D immunotherapy. We engineered a Chimeric Antigen Receptor (CAR) expressing a single-chain Fv recognizing the human pancreatic endocrine marker, HPi2. Human T cells, transduced with the resultant HPi2-CAR, proliferated and amplified Granzyme B accumulation when co-cultured with human, but not mouse β cells. Furthermore, following exposure of HPi2-CAR transduced cells to islets, CD8+ lymphocytes demonstrated enhanced CD107a (LAMP-1) expression, while CD4+ cells produced increased levels of IL-2. HPi2-CAR Tregs failed to maintain expansion due to a persistent tonic signaling from the CAR engagement to unexpectantly HPi2 antigen present on Tregs. Overall, we show lack of functionality of HPi2-CAR and highlight the importance of careful selection of CAR recognition driver for the sustainable activity and expandability of engineered T cells.
UR - http://www.scopus.com/inward/record.url?scp=85092499697&partnerID=8YFLogxK
U2 - 10.1016/j.cellimm.2020.104224
DO - 10.1016/j.cellimm.2020.104224
M3 - Article
C2 - 33068914
AN - SCOPUS:85092499697
SN - 0008-8749
VL - 358
JO - Cellular Immunology
JF - Cellular Immunology
M1 - 104224
ER -