Invariant NKT cells preferentially modulate the function of CD8 alpha+ dendritic cell subset in inducing type 1 immunity against infection.
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.
Joyee
Antony George
AG
Department of Medical Microbiology, Laboratory for Infection and Immunity, Faculty of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada.
Uzonna
Jude
J
Yang
Xi
X
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
D016827:CD8 Antigens; C409469:CD8 antigen, alpha chain