Antigen-specific CD4 T-cell help rescues exhausted CD8 T cells during chronic viral infection

Proc Natl Acad Sci U S A. 2011 Dec 27;108(52):21182-7. doi: 10.1073/pnas.1118450109. Epub 2011 Dec 12.

Abstract

CD4 T cells play a critical role in regulating CD8 T-cell responses during chronic viral infection. Several studies in animal models and humans have shown that the absence of CD4 T-cell help results in severe dysfunction of virus-specific CD8 T cells. However, whether function can be restored in already exhausted CD8 T cells by providing CD4 T-cell help at a later time remains unexplored. In this study, we used a mouse model of chronic lymphocytic choriomeningitis virus (LCMV) infection to address this question. Adoptive transfer of LCMV-specific CD4 T cells into chronically infected mice restored proliferation and cytokine production by exhausted virus-specific CD8 T cells and reduced viral burden. Although the transferred CD4 T cells were able to enhance function in exhausted CD8 T cells, these CD4 T cells expressed high levels of the programmed cell death (PD)-1 inhibitory receptor. Blockade of the PD-1 pathway increased the ability of transferred LCMV-specific CD4 T cells to produce effector cytokines, improved rescue of exhausted CD8 T cells, and resulted in a striking reduction in viral load. These results suggest that CD4 T-cell immunotherapy alone or in conjunction with blockade of inhibitory receptors may be a promising approach for treating CD8 T-cell dysfunction in chronic infections and cancer.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adoptive Transfer
  • Animals
  • Arenaviridae Infections / immunology*
  • CD4-Positive T-Lymphocytes / immunology*
  • CD4-Positive T-Lymphocytes / metabolism
  • CD4-Positive T-Lymphocytes / transplantation
  • CD8-Positive T-Lymphocytes / immunology*
  • Cytokines / immunology
  • Enzyme-Linked Immunosorbent Assay
  • Female
  • Flow Cytometry
  • Immunotherapy / methods*
  • Lymphocytic choriomeningitis virus*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Programmed Cell Death 1 Receptor / metabolism
  • Statistics, Nonparametric

Substances

  • Cytokines
  • Programmed Cell Death 1 Receptor