Immunology: Cytotoxic T cells that escape exhaustion.

Abstract

T cells of the immune system mount antiviral responses, but if a response fails, a chronic viral infection can develop. It now seems that a T-cell subset in lymphoid immune tissues can control chronic infection. See Letters p.412 & p.417 The long-term persistence of viral antigens drives the functional exhaustion of effector CD8+ T cells, yet the exhausted cells can still achieve a level of pathogen control during a chronic viral infection. Two groups reporting in this issue of Nature examine the mechanisms underlying the antiviral role of these immune cells. In a study of a mouse model of chronic lymphocytic choriomeningitis virus (LCMV) infection and human HIV patients, Lilin Ye and colleagues report a population of partially exhausted CXCR5+ CD8+ T cells that is induced by chronic virus infection, resides in B-cell follicles, and controls viral replication. Differentiation and effector function of virus-specific CXCR5+ CD8+ T cells is regulated by the Id2–E2A signalling axis. Anti-PD-L1 antibody treatment is shown to inhibit viral replication in mice synergistically with adoptively transferred CXCR5+ CD8+ T cells. Rafi Ahmed and colleagues show that chronic LCMV infection in mice promotes a population of virus-specific CD8+ T cells with a T follicular helper (TFH)-like signature. These T cells expressed the PD-1 inhibitory receptor but also expressed co-stimulatory molecules and had a gene signature that was related to CD8+ T-cell memory precursor cells and hematopoietic stem cells. These findings provide a better understanding of T-cell exhaustion and have implications towards optimizing PD-1-directed immunotherapy.