Follicular CXCR5- Expressing CD8(+) T Cells Curtail Chronic Viral Infection

Nature. 2016 Aug 2;537(7620):412-428. doi: 10.1038/nature19317.

Abstract

During chronic viral infection, virus-specific CD8(+) T cells become exhausted, exhibit poor effector function and lose memory potential. However, exhausted CD8(+) T cells can still contain viral replication in chronic infections, although the mechanism of this containment is largely unknown. Here we show that a subset of exhausted CD8(+) T cells expressing the chemokine receptor CXCR5 has a critical role in the control of viral replication in mice that were chronically infected with lymphocytic choriomeningitis virus (LCMV). These CXCR5(+) CD8(+) T cells were able to migrate into B-cell follicles, expressed lower levels of inhibitory receptors and exhibited more potent cytotoxicity than the CXCR5(-) [corrected] subset. Furthermore, we identified the Id2-E2A signalling axis as an important regulator of the generation of this subset. In patients with HIV, we also identified a virus-specific CXCR5(+) CD8(+) T-cell subset, and its number was inversely correlated with viral load. The CXCR5(+) subset showed greater therapeutic potential than the CXCR5(-) [corrected] subset when adoptively transferred to chronically infected mice, and exhibited synergistic reduction of viral load when combined with anti-PD-L1 treatment. This study defines a unique subset of exhausted CD8(+) T cells that has a pivotal role in the control of viral replication during chronic viral infection.

MeSH terms

  • Adoptive Transfer
  • Animals
  • B-Lymphocytes / immunology
  • Basic Helix-Loop-Helix Transcription Factors / metabolism
  • CD8-Positive T-Lymphocytes / cytology
  • CD8-Positive T-Lymphocytes / immunology*
  • CD8-Positive T-Lymphocytes / metabolism*
  • CD8-Positive T-Lymphocytes / transplantation
  • Cell Differentiation
  • Chronic Disease
  • Female
  • Germinal Center / cytology*
  • Germinal Center / immunology
  • HIV Infections / immunology
  • HIV Infections / virology
  • Humans
  • Inhibitor of Differentiation Protein 2 / metabolism
  • Lymphocytic Choriomeningitis / immunology*
  • Lymphocytic Choriomeningitis / virology*
  • Lymphocytic choriomeningitis virus / growth & development
  • Lymphocytic choriomeningitis virus / immunology*
  • Male
  • Mice
  • Receptors, CXCR5 / deficiency
  • Receptors, CXCR5 / metabolism*
  • Signal Transduction
  • T-Lymphocyte Subsets / cytology
  • T-Lymphocyte Subsets / immunology
  • T-Lymphocyte Subsets / metabolism
  • T-Lymphocyte Subsets / transplantation
  • Viral Load / immunology
  • Virus Replication / immunology

Substances

  • Basic Helix-Loop-Helix Transcription Factors
  • CXCR5 protein, mouse
  • Idb2 protein, mouse
  • Inhibitor of Differentiation Protein 2
  • Receptors, CXCR5
  • Tcf3 protein, mouse