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

Rachael D. Aubert, Alice O. Kamphorst, Surojit Sarkar, Vaiva Vezys, Sang Jun Ha, Daniel L. Barber, Lilin Ye, Arlene H. Sharpe, Gordon J. Freeman, Rafi Ahmed

Research output: Contribution to journalArticlepeer-review

106 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)21182-21187
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume108
Issue number52
DOIs
StatePublished - Dec 27 2011

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