title: Molecular basis for the potency of IL-10-deficient dendritic cells as a highly efficient APC system for activating Th1 response.
abstract: Identification and targeting of novel immunobiological factors that regulate the induction of Th1 cells are crucial for designing effective vaccines against certain intracellular pathogens, including Chlamydia. IL-10-deficient dendritic cells (DC) are potent APCs and effective cellular vaccines that activate a high frequency of specific Th1 cells. To elucidate the molecular basis for the potency of the IL-10-deficient APC system, we tested the hypothesis that Chlamydia Ag-primed IL-10 knockout (IL-10KO) DC are quantitatively and qualitatively distinct in their metabolic characteristics relating to T cell activation. Using a combination of RT-PCR, two-dimensional gel electrophoresis, and MALDI-TOF-based proteomics analyses, the transcriptional and translational activities of Chlamydia-pulsed DC from wild-type and IL-10KO mice were assessed. IL-10 deficiency caused early maturation and activation of pulsed DC (i.e., high CD11c, CD40, CD80, CD83, CD86, IL-1, IL-12, and the T cell-attracting chemokine CCL27/CTACK) and consequently an enhanced ability to process and present Ags for a rapid and robust T cell activation. Supporting comparative proteomics revealed further that IL-10 deficient DC possess specific immunobiological properties, e.g., the T cell-attracting chemokine CCL27/CTACK, calcium-dependent protein kinase, and the IL-1/IL-12 inducer, NKR-P1A (CD161), which differentiated them immunologically from wild-type DC that express molecules relating to anti-inflammatory, differentiative, and metabolic processes, e.g., the anti-IL-12 molecule peroxisome proliferator-activated receptor-alpha and thymidine kinase. Collectively, these results provide a molecular basis for the high Th1-activating capacity of IL-10KO APC and may provide unique immunomodulation targets when designing vaccines against pathogens controlled by T cell immunity.
authors.affiliation: Morehouse School of Medicine, Atlanta, GA 30310, USA.
authors.forename: Qing
authors.initials: Q
authors.lastname: He
authors.forename: Terri T
authors.initials: TT
authors.lastname: Moore
authors.forename: Francis O
authors.initials: FO
authors.lastname: Eko
authors.forename: Deborah
authors.initials: D
authors.lastname: Lyn
authors.forename: Godwin A
authors.initials: GA
authors.lastname: Ananaba
authors.forename: Amy
authors.initials: A
authors.lastname: Martin
authors.forename: Shailesh
authors.initials: S
authors.lastname: Singh
authors.forename: Lillard
authors.initials: L
authors.lastname: James
authors.forename: Jonathan
authors.initials: J
authors.lastname: Stiles
authors.forename: Carolyn M
authors.initials: CM
authors.lastname: Black
authors.forename: Joseph U
authors.initials: JU
authors.lastname: Igietseme
mesh_terms: D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology*; D000942:Antigens, Bacterial; D023502:Chlamydia muridarum / Q000276:immunology / Q000472:pathogenicity; D002692:Chlamydia trachomatis / Q000276:immunology / Q000472:pathogenicity; D003713:Dendritic Cells / Q000276:immunology*; D005260:Female; D007371:Interferon-gamma / Q000378:metabolism; D016753:Interleukin-10 / Q000172:deficiency* / Q000235:genetics; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D040901:Proteomics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018417:Th1 Cells / Q000276:immunology*
chemical_list: D000942:Antigens, Bacterial; D012333:RNA, Messenger; D016753:Interleukin-10; D007371:Interferon-gamma