title: Human plasmacytoid dendritic cells efficiently capture HIV-1 envelope glycoproteins via CD4 for antigen presentation.
abstract: Advances in HIV-1 vaccine clinical trials and preclinical research indicate that the virus envelope glycoproteins (Env) are likely to be an essential component of a prophylactic vaccine. Efficient Ag uptake and presentation by dendritic cells (DCs) is important for strong CD4(+) Th cell responses and the development of effective humoral immune responses. In this study, we examined the capacity of distinct primary human DC subsets to internalize and present recombinant Env to CD4(+) T cells. Consistent with their specific receptor expression, skin DCs bound and internalized Env via C-type lectin receptors, whereas blood DC subsets, including CD1c(+) myeloid DCs, CD123(+) plasmacytoid DCs (PDCs), and CD141(+) DCs exhibited a restricted repertoire of C-type lectin receptors and relied on CD4 for uptake of Env. Despite a generally poor capacity for Ag uptake compared with myeloid DCs, the high expression of CD4 on PDCs allowed them to bind and internalize Env very efficiently. CD4-mediated uptake delivered Env to EEA1(+) endosomes that progressed to Lamp1(+) and MHC class II(+) lysosomes where internalized Env was degraded rapidly. Finally, all three blood DC subsets were able to internalize an Env-CMV pp65 fusion protein via CD4 and stimulate pp65-specific CD4(+) T cells. Thus, in the in vitro systems described in this paper, CD4-mediated uptake of Env is a functional pathway leading to Ag presentation, and this may therefore be a mechanism used by blood DCs, including PDCs, for generating immune responses to Env-based vaccines.
authors.affiliation: Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, 141 86 Stockholm, Sweden.
authors.forename: Kerrie J
authors.initials: KJ
authors.lastname: Sandgren
authors.forename: Anna
authors.initials: A
authors.lastname: Smed-Sörensen
authors.forename: Mattias N
authors.initials: MN
authors.lastname: Forsell
authors.forename: Martina
authors.initials: M
authors.lastname: Soldemo
authors.forename: William C
authors.initials: WC
authors.lastname: Adams
authors.forename: Frank
authors.initials: F
authors.lastname: Liang
authors.forename: Leif
authors.initials: L
authors.lastname: Perbeck
authors.forename: Richard A
authors.initials: RA
authors.lastname: Koup
authors.forename: Richard T
authors.initials: RT
authors.lastname: Wyatt
authors.forename: Gunilla B
authors.initials: GB
authors.lastname: Karlsson Hedestam
authors.forename: Karin
authors.initials: K
authors.lastname: Loré
mesh_terms: D017951:Antigen Presentation / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000821:virology*; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism / Q000821:virology*; D015699:HIV Envelope Protein gp120 / Q000097:blood / Q000276:immunology* / Q000378:metabolism; D015497:HIV-1 / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D037181:Lectins, C-Type / Q000276:immunology / Q000378:metabolism; D011485:Protein Binding / Q000276:immunology; D021381:Protein Transport / Q000276:immunology; D012867:Skin / Q000276:immunology / Q000378:metabolism / Q000821:virology
chemical_list: D015699:HIV Envelope Protein gp120; D037181:Lectins, C-Type; C514793:gp120 protein, Human immunodeficiency virus 1