a role for the chemokine rantes in regulating cd8 t cell responses during chronic viral infection趋化因子的作用在调节cd8 t细胞反应咆哮慢性病毒感染.pdfVIP

A Role for the Chemokine RANTES in Regulating CD8 T Cell Responses during Chronic Viral Infection 1 1 2 1 1 Alison Crawford , Jill Marie Angelosanto , Kim Lynn Nadwodny , Shawn D. Blackburn , E. John Wherry * 1 Department of Microbiology and Institute for Immunology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, United States of America, 2 GlaxoSmithKline, Department of Safety Assessment, Immunologic Toxicology, King of Prussia, Pennsylvania, United States of America Abstract RANTES (CCL5) is a chemokine expressed by many hematopoietic and non-hematopoietic cell types that plays an important role in homing and migration of effector and memory T cells during acute infections. The RANTES receptor, CCR5, is a major target of anti-HIV drugs based on blocking viral entry. However, defects in RANTES or RANTES receptors including CCR5 can compromise immunity to acute infections in animal models and lead to more severe disease in humans infected with west Nile virus (WNV). In contrast, the role of the RANTES pathway in regulating T cell responses and immunity during chronic infection remains unclear. In this study, we demonstrate a crucial role for RANTES in the control of systemic chronic LCMV infection. In RANTES2/ 2 mice, virus-specific CD8 T cells had poor cytokine production. These RANTES2/ 2 CD8 T cells also expressed higher amounts of inhibitory receptors consistent with more severe exhaustion. Moreover, the cytotoxic ability of CD8 T cells from RANTES2/ 2 mice was reduced. Consequently, viral load was higher in the absence of RANTES. The dysfunction of T cells in the absence of RANTES was as severe as CD8 T cell