IL-12 acts selectively on CD8 alpha- dendritic cells to enhance presentation of a tumor peptide in vivo.
Previous work has shown that a significant proportion of murine splenic dendritic cells (DC) express a high affinity receptor for IL-12, thus accounting for the adjuvanticity of the cytokine when DBA/2 mice are transferred with syngeneic DC exposed in vitro to rIL-12 and an otherwise poorly immunogenic tumor peptide. In DBA/2 mice, splenic DC consist of 90-95% CD8- and 5-10% CD8+ cells. To detect any difference in IL-12 responsiveness among phenotypically distinct DC subtypes, enriched CD8- (>99% pure) and CD8+ ( approximately 80% pure) populations of DC from DBA/2 spleens were assayed for APC function in vivo following exposure to rIL-12 and tumor peptide in vitro. Unlike unfractionated DC, the CD8- fraction was capable of effective presentation of the peptide even when the cells had not been pretreated with IL-12 before peptide pulsing. The addition of as few as 3% CD8+ cells during pulsing blocked in vivo priming by the CD8- fraction. However, pretreatment of CD8- DC with IL-12 before cell mixing and peptide pulsing ablated the inhibitory effect of the CD8+ fraction. CD8-, but not CD8+, DC showed significant message expression for the beta 1 and beta 2 subunits of the IL-12 receptor. These data suggest that a minority population of CD8+ DC, which appeared to secrete IL-10 in vitro, negatively regulates the induction of T cell reactivity by peptide-loaded CD8- DC in DBA/2 mice. However, the CD8- fraction can be primed by IL-12 to overcome the inhibitory effect of the CD8+ subtype.
Grohmann
U
U
Department of Experimental Medicine and Pharmacology, University of Perugia, Italy.
Bianchi
R
R
Belladonna
M L
ML
Vacca
Carmine
C
Silla
S
S
Ayroldi
E
E
Fioretti
M C
MC
Puccetti
P
P
D000818:Animals; D017951:Antigen Presentation / Q000276:immunology*; D000951:Antigens, Neoplasm / Q000008:administration & dosage* / Q000276:immunology* / Q000378:metabolism; D016827:CD8 Antigens / Q000096:biosynthesis*; D017635:Clonal Anergy / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism; D006968:Hypersensitivity, Delayed / Q000276:immunology / Q000517:prevention & control; D007114:Immunization; D007275:Injections, Intravenous; D016753:Interleukin-10 / Q000096:biosynthesis / Q000235:genetics; D018664:Interleukin-12 / Q000378:metabolism / Q000502:physiology*; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D009842:Oligopeptides / Q000008:administration & dosage* / Q000276:immunology* / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis; D018123:Receptors, Interleukin / Q000096:biosynthesis / Q000235:genetics; D053707:Receptors, Interleukin-12; D011994:Recombinant Proteins / Q000494:pharmacology
D000951:Antigens, Neoplasm; D016827:CD8 Antigens; D009842:Oligopeptides; D012333:RNA, Messenger; D018123:Receptors, Interleukin; D053707:Receptors, Interleukin-12; D011994:Recombinant Proteins; C076546:tumor rejection antigen P815A, mouse; D016753:Interleukin-10; D018664:Interleukin-12