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The Role for Monocyte Chemoattractant Protein-1 in the Generation and Function of Memory CD8⁺ T Cells¹

Center for Biomedical Research, University of Texas Health Center, Tyler, TX 75708

Memory T cells are resistant to the conventional costimulatory blockade and therefore impede tolerance induction. However, their migratory, survival, and functional requirements for chemokines are not well understood. We herein examine the role for MCP-1 or CCL2 in the generation, migration, and function of memory CD8⁺ T cells. We found that overall generation of both central memory (T_CM) and effector memory (T_EM) CD8⁺ T cells was severely impaired in the absence of MCP-1. Importantly, the survival of T_EM, but not T_CM, CD8⁺ cells was reduced without MCP-1, whereas the homeostatic proliferation of T_CM, but not T_EM, CD8⁺ cells was weakened in MCP-1^–/– mice. However, once they were generated in the absence of MCP-1, in vitro function of both subsets of memory cells remained intact as determined by their proliferation and IFN- production. Interestingly, the migration of T_CM, but not T_EM, CD8⁺ cells to inflammatory sites was significantly delayed without MCP-1, whereas both subsets of memory cells underwent comparable expansion and apoptosis with or without MCP-1 during the effector phase. Moreover, the function to eliminate a graft of T_CM, but not T_EM, CD8⁺ cells was impaired without MCP-1. Thus, this study demonstrates that MCP-1 plays an important role in not only migration but also generation and survival of memory T cells. This finding provides new insight into the requirement of chemokines for the generation, survival, and function of differential subsets of memory T cells and may have clinic implications for tolerance induction.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by research grants from the Juvenile Diabetes Research Foundation International and from the American Diabetes Association.

² Current address: Department of Parasitology, Sichuan University, 17 Third Section of Ren Min Nan Lu, Chengdu, Sichuan Province 610041, China.

³ Address correspondence and reprint requests to Dr. Zhenhua Dai, University of Texas Health Center, 11937 U.S. Highway 271, Tyler, TX 75708. E-mail address: zhenhua.dai{at}uthct.edu

⁴ Abbreviations used in this paper: T_EM, effector memory T cells; T_CM, central memory T cells; mLN, mesenteric lymph node.