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Bystander Central Memory but Not Effector Memory CD8⁺ T Cells Suppress Allograft Rejection¹

Ni Wan^*, Hehua Dai^*, Tao Wang^*, Yolonda Moore^*, Xin Xiao Zheng and Zhenhua Dai^2,*

^* Center for Biomedical Research, University of Texas Health Center, Tyler, TX 75708; and Division of Immunology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215

Memory T cells respond faster and more vigorously than their naive counterparts and are critical for adaptive immunity. However, it is unknown whether and how memory T cells react in the face of irrelevant Ags. It is generally accepted that bystander memory T cells are neutral in immune responsiveness. In this study, we present the first evidence that bystander central memory (T_CM), but not effector memory (T_EM), CD8⁺ T cells suppress allograft rejection as well as T cell proliferation in the draining lymph nodes (DLN) of recipient mice. Both bystander T_CM and naive T cells, but fewer T_EM cells, migrated to DLN, whereas T_CM cells exhibited faster turnover than their naive counterparts, suggesting that bystander T_CM cells have an advantage over their naive counterparts in suppression. However, bystander T_EM cells migrated to inflammatory graft sites, but not DLN, and yet failed to exert their suppression. These findings indicate that bystander memory T cells need to migrate to lymph nodes to exert their suppression by inhibiting responder T cell activation or homeostatic proliferation. Moreover, the suppression mediated by bystander T_CM cells was largely dependent on IL-15, as IL-15 was required for their homeostatic proliferation and T_CM-mediated suppression of allograft rejection. This suppression also required the presence of TGFβ1, as T_CM cells expressed TGFβ1 while neutralizing TGFβ1 abolished their suppression. Thus, bystander T_CM, but not T_EM, CD8⁺ T cells are potent suppressors rather than bystanders. This new finding will have an impact on cellular immunology 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 Juvenile Diabetes Research Foundation International and from American Diabetes Association.

² 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

³ Abbreviations used in this paper: Treg, regulatory T cell; T_EM, effector memory T cell; T_CM, central memory T cell; WT, wild type; DLN, draining lymph nodes; MST, median survival time.