IL-2Rα mediates temporal regulation of IL-2 signaling and enhances immunotherapy
作者： Ee W. Su , Caitlin J. Moore , Samantha Suriano , Christopher Bryce Johnson , Neizel Songalia
DOI: 10.1126/SCITRANSLMED.AAC8155
关键词:
摘要: Interleukin-2 (IL-2) is a lymphocyte growth factor that an important component of many immune-based cancer therapies. The efficacy IL-2 thought to be limited by the expansion T regulatory cells, which express high-affinity receptor subunit IL-2Rα. IL-15 under investigation as alternative IL-2. Although both cytokines signal through IL-2Rβγ, does not bind IL-2Rα and therefore induces less cell expansion. However, we found transferred effector CD8(+) cells induced curative responses in lymphoreplete mice only with IL-2-based therapy. conventional vitro assays showed similar responsiveness IL-15, upon removal free cytokine, mediated sustained signaling dependent on Mechanistically, promoting surface reservoir recycling back surface. Our results demonstrate endows ability compete temporally for via mechanisms beyond ligand affinity. These suggest strategies enhance expression tumor-reactive lymphocytes may facilitate development more effective
sciencemag.org参考文章(33)
O Marker, A R Thomsen, J P Christensen, E C Andersson, Changes in cell adhesion molecule expression on T cells associated with systemic virus infection. Journal of Immunology. ,vol. 152, pp. 1237- 1245 ,(1994)
A. Loomis, K. Shanebeck, R. DuBose, D. Cosman, L. S. Park, D. M. Anderson, J. G. Giri, S. Kumaki, M. Ahdieh, D. J. Friend, Identification and cloning of a novel IL-15 binding protein that is structurally related to the alpha chain of the IL-2 receptor. The EMBO Journal. ,vol. 14, pp. 3654- 3663 ,(1995) , 10.1002/J.1460-2075.1995.TB00035.X
Jamie B Spangler, Jakub Tomala, Vincent C Luca, Kevin M Jude, Shen Dong, Aaron M Ring, Petra Votavova, Marion Pepper, Marek Kovar, K Christopher Garcia, None, Antibodies to Interleukin-2 elicit selective T cell subset potentiation through distinct conformational mechanisms Immunity. ,vol. 42, pp. 815- 825 ,(2015) , 10.1016/J.IMMUNI.2015.04.015
J. J. Obar, M. J. Molloy, E. R. Jellison, T. A. Stoklasek, W. Zhang, E. J. Usherwood, L. Lefrancois, CD4+ T cell regulation of CD25 expression controls development of short-lived effector CD8+ T cells in primary and secondary responses Proceedings of the National Academy of Sciences of the United States of America. ,vol. 107, pp. 193- 198 ,(2010) , 10.1073/PNAS.0909945107
R J Robb, W C Greene, Internalization of interleukin 2 is mediated by the beta chain of the high-affinity interleukin 2 receptor. Journal of Experimental Medicine. ,vol. 165, pp. 1201- 1206 ,(1987) , 10.1084/JEM.165.4.1201
Dennis M. Willerford, Jianzhu Chen, Judith A. Ferry, Laurie Davidson, Averil Ma, Frederick W. Alt, Interleukin-2 receptor α chain regulates the size and content of the peripheral lymphoid compartment Immunity. ,vol. 3, pp. 521- 530 ,(1995) , 10.1016/1074-7613(95)90180-9
Onur Boyman, Marek Kovar, Mark P Rubinstein, Charles D Surh, Jonathan Sprent, Selective stimulation of T cell subsets with antibody-cytokine immune complexes Science. ,vol. 311, pp. 1924- 1927 ,(2006) , 10.1126/SCIENCE.1122927
Benjamin Sadlack, Hartmut Merz, Hubert Schorle, Anneliese Schimpl, Alfred C. Feller, Ivan Horak, Ulcerative colitis-like disease in mice with a disrupted interleukin-2 gene. Cell. ,vol. 75, pp. 253- 261 ,(1993) , 10.1016/0092-8674(93)80067-O
Wei Liao, Jian-Xin Lin, Warren J. Leonard, Interleukin-2 at the Crossroads of Effector Responses, Tolerance, and Immunotherapy Immunity. ,vol. 38, pp. 13- 25 ,(2013) , 10.1016/J.IMMUNI.2013.01.004
Aaron M Ring, Jian-Xin Lin, Dan Feng, Suman Mitra, Mathias Rickert, Gregory R Bowman, Vijay S Pande, Peng Li, Ignacio Moraga, Rosanne Spolski, Engin Özkan, Warren J Leonard, K Christopher Garcia, None, Mechanistic and structural insight into the functional dichotomy between IL-2 and IL-15 Nature Immunology. ,vol. 13, pp. 1187- 1195 ,(2012) , 10.1038/NI.2449