Bystander central memory but not effector memory CD8⁺ T cells suppress allograft rejection

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.