Distinct roles for IL-6 and IL-12p40 in mediating protection against Leishmania donovani and the expansion of IL-10+ CD4+ T cells.
Adoptive dendritic cell (DC) immunotherapy provides a useful experimental tool to evaluate immunoregulation in vivo and has previously been successfully used to enhance host resistance in a variety of experimental models of leishmaniasis. Here, we used this approach to identify IL-6 and IL-12p40 as critical cytokines that cooperate to mediate host protection to Leishmania donovani but which act independently to regulate expansion of IL-10(+) CD4(+) T cells, shown here for the first time to be associated with this infection. Adoptive transfer of LPS-activated bone marrow-derived DC (BMDC) from wild-type mice was therapeutically beneficial and led to enhanced resistance as measured by spleen parasite burden. In contrast, IL-6- or IL-12p40-deficient BMDC had no protective benefit, indicating that production of both cytokines was essential for the therapeutic efficacy of DC. IL-10 production by CD25(-) FoxP3(-) IL-10(+) CD4(+) T cells is a strong correlate of disease progression, and BMDC from wild-type mice inhibited expansion of these cells. Strikingly, IL-12-deficient BMDC could also inhibit the expansion of this T cell population whereas IL-6-deficient BMDC could not, indicating that IL-6 played a key role in this aspect of DC function in vivo. Breadth of cytokine production is thus an important factor when considering strategies for DC-based interventions.
Stäger
Simona
S
Immunology and Infection Unit, Hull York Medical School and Department of Biology, University of York, York, UK.
Maroof
Asher
A
Zubairi
Soombul
S
Sanos
Stephanie L
SL
Kopf
Manfred
M
Kaye
Paul M
PM
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology; D049109:Cell Proliferation; D003713:Dendritic Cells / Q000276:immunology / Q000637:transplantation; D007113:Immunity, Innate / Q000235:genetics; D016219:Immunotherapy, Adoptive; D016753:Interleukin-10 / Q000096:biosynthesis*; D018664:Interleukin-12 / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D053762:Interleukin-12 Subunit p40; D015850:Interleukin-6 / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D007893:Leishmania donovani / Q000276:immunology*; D007898:Leishmaniasis, Visceral / Q000276:immunology* / Q000628:therapy; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D021122:Protein Subunits / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000502:physiology*
D053762:Interleukin-12 Subunit p40; D015850:Interleukin-6; D021122:Protein Subunits; D016753:Interleukin-10; D018664:Interleukin-12