title: Enhancement of HIV-specific CD8 T cell responses by dual costimulation with CD80 and CD137L.
abstract: HIV-specific CD8 T cell responses are defective in chronic HIV infection. In this study, we report that costimulation with either CD137L (4-1BBL) or CD80 (B7.1) enhanced the Ag-specific expansion and acquisition of effector function by HIV-specific memory CD8 T cells. Ag-specific T cells from recently infected donors showed maximal expansion with single costimulatory molecules. Dual costimulation of T cells from recently infected donors or from healthy donors responding to influenza epitopes led to enhanced responses when the accumulation of cytokines was measured. However, accumulation of regulatory cytokines, particularly IFN-gamma, led to inhibition of further Ag-specific CD8 T cell expansion in the cultures. This inhibition was relieved by neutralization of IFN-gamma or of IFN-gamma, TNF, and IL-10. Thus, strong costimulation of T cells in vitro can lead to induction of regulatory cytokines at levels that limit further T cell expansion. In marked contrast, T cells from long-term (>4 years) infected HIV+ donors exhibited reduced Ag-specific CD8 T cell expansion, reduced CD4 T cell responses, and minimal cytokine accumulation. Dual costimulation with both 4-1BBL and B7.1 enhanced responses of T cells from long-term infected subjects to a level similar to that obtained with T cells from early in HIV infection. Experiments with purified CD8 T cells showed that B7.1 and 4-1BBL could act directly and synergistically on CD8 T cells. Taken together, these data suggest that 4-1BBL and B7.1 have additive or synergistic effects on HIV-specific CD8 T cell responses and represent a promising combination for therapeutic vaccination for HIV.
authors.affiliation: Department of Immunology, University of Toronto, Toronto, Canada.
authors.forename: Jacob
authors.initials: J
authors.lastname: Bukczynski
authors.forename: Tao
authors.initials: T
authors.lastname: Wen
authors.forename: Chao
authors.initials: C
authors.lastname: Wang
authors.forename: Natasha
authors.initials: N
authors.lastname: Christie
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Routy
authors.forename: Mohamed-Rachid
authors.initials: MR
authors.lastname: Boulassel
authors.forename: Colin M
authors.initials: CM
authors.lastname: Kovacs
authors.forename: Kelly S
authors.initials: KS
authors.lastname: Macdonald
authors.forename: Mario
authors.initials: M
authors.lastname: Ostrowski
authors.forename: Rafick-Pierre
authors.initials: RP
authors.lastname: Sekaly
authors.forename: Nicole F
authors.initials: NF
authors.lastname: Bernard
authors.forename: Tania H
authors.initials: TH
authors.lastname: Watts
mesh_terms: D053330:4-1BB Ligand; D000938:Antigen-Presenting Cells / Q000276:immunology; D018122:B7-1 Antigen / Q000008:administration & dosage / Q000235:genetics / Q000378:metabolism*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D006678:HIV / Q000276:immunology*; D015658:HIV Infections / Q000276:immunology; D006801:Humans; D066298:In Vitro Techniques; D008213:Lymphocyte Activation; D008562:Membrane Glycoproteins / Q000378:metabolism; D054353:Perforin; D052899:Pore Forming Cytotoxic Proteins; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000235:genetics / Q000378:metabolism; D013997:Time Factors; D048069:Tumor Necrosis Factors / Q000008:administration & dosage / Q000235:genetics / Q000378:metabolism*
chemical_list: D053330:4-1BB Ligand; D018122:B7-1 Antigen; D016207:Cytokines; D008562:Membrane Glycoproteins; D052899:Pore Forming Cytotoxic Proteins; D011994:Recombinant Proteins; C505974:TNFSF9 protein, human; D048069:Tumor Necrosis Factors; D054353:Perforin