title: Antigen-specific CD4 T-cell help rescues exhausted CD8 T cells during chronic viral infection.
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.
authors.affiliation: Emory Vaccine Center and Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors.forename: Rachael D
authors.initials: RD
authors.lastname: Aubert
authors.forename: Alice O
authors.initials: AO
authors.lastname: Kamphorst
authors.forename: Surojit
authors.initials: S
authors.lastname: Sarkar
authors.forename: Vaiva
authors.initials: V
authors.lastname: Vezys
authors.forename: Sang-Jun
authors.initials: SJ
authors.lastname: Ha
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Barber
authors.forename: Lilin
authors.initials: L
authors.lastname: Ye
authors.forename: Arlene H
authors.initials: AH
authors.lastname: Sharpe
authors.forename: Gordon J
authors.initials: GJ
authors.lastname: Freeman
authors.forename: Rafi
authors.initials: R
authors.lastname: Ahmed
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D001117:Arenaviridae Infections / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000637:transplantation; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D016207:Cytokines / Q000276:immunology; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D007167:Immunotherapy / Q000379:methods*; D008217:Lymphocytic choriomeningitis virus; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D061026:Programmed Cell Death 1 Receptor / Q000378:metabolism; D018709:Statistics, Nonparametric
chemical_list: D016207:Cytokines; D061026:Programmed Cell Death 1 Receptor