Journal Article

Defining CD8+ T cells that provide the proliferative burst after PD-1 therapy

Nakaya, Helder I., Lee, Junghwa, Germain, Ronald N., Ahmed, Rafi, Nasti, Tahseen H., Im, Se Jin, Kissick, Haydn T., Sharpe, Arlene H., Freeman, Gordon J., Lee, Judong, Gerner, Michael Y., Shan, Qiang, Hashimoto, Masao, Hale, J. Scott, Burger, Matheus C., Xue, Hai-Hui

2016

Overview

Chronic infection with lymphocytic choriomeningitis virus promotes the establishment of a population of stem-like PD-1 + CD8 + T cells that reside in lymphoid tissues and preferentially expand when the PD-1 inhibitory pathway is blocked. CD8 + T cells controlling chronic viral infections 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 (T FH )-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. Chronic viral infections are characterized by a state of CD8 + T-cell dysfunction that is associated with expression of the programmed cell death 1 (PD-1) inhibitory receptor 1 , 2 , 3 , 4 . A better understanding of the mechanisms that regulate CD8 + T-cell responses during chronic infection is required to improve immunotherapies that restore function in exhausted CD8 + T cells. Here we identify a population of virus-specific CD8 + T cells that proliferate after blockade of the PD-1 inhibitory pathway in mice chronically infected with lymphocytic choriomeningitis virus (LCMV). These LCMV-specific CD8 + T cells expressed the PD-1 inhibitory receptor, but also expressed several costimulatory molecules such as ICOS and CD28. This CD8 + T-cell subset was characterized by a unique gene signature that was related to that of CD4 + T follicular helper (T FH ) cells, CD8 + T cell memory precursors and haematopoietic stem cell progenitors, but that was distinct from that of CD4 + T H 1 cells and CD8 + terminal effectors. This CD8 + T-cell population was found only in lymphoid tissues and resided predominantly in the T-cell zones along with naive CD8 + T cells. These PD-1 + CD8 + T cells resembled stem cells during chronic LCMV infection, undergoing self-renewal and also differentiating into the terminally exhausted CD8 + T cells that were present in both lymphoid and non-lymphoid tissues. The proliferative burst after PD-1 blockade came almost exclusively from this CD8 + T-cell subset. Notably, the transcription factor TCF1 had a cell-intrinsic and essential role in the generation of this CD8 + T-cell subset. These findings provide a better understanding of T-cell exhaustion and have implications in the optimization of PD-1-directed immunotherapy in chronic infections and cancer.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 631/250/2152/1566 / 631/250/255/2514 / Animals / Care and treatment / CD28 Antigens - metabolism / CD8-Positive T-Lymphocytes - cytology / CD8-Positive T-Lymphocytes - drug effects / CD8-Positive T-Lymphocytes - immunology / CD8-Positive T-Lymphocytes - metabolism / Cell Differentiation / Cell Proliferation - drug effects / Cell Self Renewal / Development and progression / Female / Health aspects / Hematopoietic Stem Cells - cytology / Hematopoietic Stem Cells - immunology / Hepatocyte Nuclear Factor 1-alpha - metabolism / Humanities and Social Sciences / Immunotherapy / Inducible T-Cell Co-Stimulator Protein - metabolism / letter / Lymphocytic Choriomeningitis / Lymphocytic choriomeningitis virus - immunology / Lymphocytic choriomeningitis virus - physiology / Methods / Mice / multidisciplinary / Programmed Cell Death 1 Receptor - antagonists & inhibitors / Programmed Cell Death 1 Receptor - metabolism / Science / T cells / T-Lymphocyte Subsets - cytology / T-Lymphocyte Subsets - drug effects / T-Lymphocyte Subsets - immunology / T-Lymphocyte Subsets - metabolism / T-Lymphocytes, Helper-Inducer - metabolism / Virus diseases