@article {542191, title = {Antigen-specific CD4 T-cell help rescues exhausted CD8 T cells during chronic viral infection.}, journal = {Proc Natl Acad Sci U S A}, volume = {108}, number = {52}, year = {2011}, month = {2011 Dec 27}, pages = {21182-7}, 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.}, keywords = {Adoptive Transfer, Animals, Arenaviridae Infections, CD4-Positive T-Lymphocytes, CD8-Positive T-Lymphocytes, Cytokines, Enzyme-Linked Immunosorbent Assay, Female, Flow Cytometry, Immunotherapy, Lymphocytic choriomeningitis virus, Mice, Mice, Inbred C57BL, Mice, Transgenic, Programmed Cell Death 1 Receptor, Statistics, Nonparametric}, issn = {1091-6490}, doi = {10.1073/pnas.1118450109}, author = {Aubert, Rachael D and Kamphorst, Alice O and Sarkar, Surojit and Vezys, Vaiva and Ha, Sang-Jun and Barber, Daniel L and Ye, Lilin and Sharpe, Arlene H and Freeman, Gordon J and Ahmed, Rafi} }