title: Invariant NKT cells preferentially modulate the function of CD8 alpha+ dendritic cell subset in inducing type 1 immunity against infection.
abstract: Although studies suggest that NKT cell (NKT) activation modulates the function of dendritic cells (DCs) in inducing T cell responses, it is unknown whether this modulating effect is biased to a DC subset. We previously reported that NKT activation could modulate DC function in inducing protective T cell immunity to Chlamydia pneumoniae, an intracellular bacterial infection. In this study, we investigated the effect of NKT activation on DC subsets, using multiple approaches, including gene knockout mice, alpha- galactosylceramide stimulation, adoptive transfer of invariant NKT (iNKT), and functional analysis of DC subsets in both in vitro and in vivo settings. We found a preferential modulating effect of iNKTs on the CD8alpha(+) DC subset. Specifically, we found that iNKT-deficient mice, compared with wild-type (WT) mice, showed reduced CD8alpha(+) DC expansion with lower CD40 expression and IL-12 production, whereas enhancing iNKT activation in WT mice or adoptive transfer of iNKTs to Jalpha18(-/-) mice resulted in increased function of CD8alpha(+) DCs in inducing type 1 immune responses. Further, DC-iNKT coculture experiments showed a direct CD40L-dependent enhancing effect of iNKTs on IL-12p70 production by CD8alpha(+) DCs. More importantly, CD8alpha(+) DCs from Jalpha18(-/-) mice, compared with those from WT mice, showed significantly reduced ability to activate IFN-gamma-producing T cells in vitro and to induce type 1 immunity and protection in vivo. Moreover, a similar CD8alpha(+) DC subset alteration was found in the Jalpha18(-/-) mice following Leishmania major infection. Our data provide the first direct evidence that iNKTs preferentially promote the functional development of a subset of DC to generate protective immunity against infections.
authors.affiliation: Department of Medical Microbiology, Laboratory for Infection and Immunity, Faculty of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada.
authors.forename: Antony George
authors.initials: AG
authors.lastname: Joyee
authors.forename: Jude
authors.initials: J
authors.lastname: Uzonna
authors.forename: Xi
authors.initials: X
authors.lastname: Yang
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D016827:CD8 Antigens / Q000096:biosynthesis*; D002478:Cells, Cultured; D016993:Chlamydophila pneumoniae / Q000276:immunology; D018920:Coculture Techniques; D003713:Dendritic Cells / Q000276:immunology* / Q000382:microbiology / Q000637:transplantation; D007111:Immunity, Cellular; D018320:Leishmania major / Q000276:immunology; D016773:Leishmaniasis, Cutaneous / Q000382:microbiology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D055611:Natural Killer T-Cells / Q000276:immunology* / Q000382:microbiology / Q000469:parasitology; D018410:Pneumonia, Bacterial / Q000276:immunology; D018417:Th1 Cells / Q000276:immunology* / Q000382:microbiology
chemical_list: D016827:CD8 Antigens; C409469:CD8 antigen, alpha chain