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-α 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.

Involvement of leptin signaling in the survival and maturation of bone marrow‐derived dendritic cells

“…Thus, the marked reduction of IL-12p70 secretion by db/db DC may result from increased IL-10 expression. Like IL-4 and TGF-b, IL-10 can act as a negative regulator to suppress the maturation and immunostimulatory capacity of DC by inhibiting CD80 and CD86 expression [36]. Since reduced IL-12 secretion prevents pre-Th cells from entering the Th1 pathway, the increased level of IL-10 in db/db DC cultures favors the polarization of naive T cells toward a Th2 phenotype.…”

Differential CD28 and Inducible Costimulatory Molecule Signaling Requirements for Protective CD4+T-Cell-Mediated Immunity against Genital TractChlamydia trachomatisInfection

“…We and others have previously shown that CD4 ϩ T cells are crucial for the clearance of a primary infection with C. trachomatis from the genital tract and the development of protective immunity (17,19,47). To assess the level of T-cell responsiveness to recall antigen (Ag), we prepared single-cell suspensions from the PALN, which were incubated with heat-inactivated chlamydial Ag.…”

NK Cells Promote Type 1 T Cell Immunity through Modulating the Function of Dendritic Cells during Intracellular Bacterial Infection

“…A recent study showed that NK cells can enhance the capacity of DC to present parasitic Ags via the NKG2D receptor pathway (21). The important role of DC in initiation and maintenance of T cell responses to chlamydial infection has been demonstrated by several previous studies using mouse models of C. trachomatis mouse pneumonitis strain, more recently called Chlamydia muridarum (22)(23)(24)(25)(26)(27)(28)(29)(30)(31). Su et al (22) reported that i.v.…”

“…In particular, by comparing DC from wild-type and IL-12 gene knockout mice, Lu and Zhong (25) found that IL-12 produced by DC is the most important cytokine in the initiation of Th1 immunity to C. muridarum lung infection. In contrast, by comparing DC from wildtype and IL-10 gene knockout mice, He et al (30) found that IL-10 production by DC was associated with inhibition of Th1 immunity to chlamydial infection. Moreover, Rey-Ladino et al (31) reported that DC with distinct phenotype and cytokine production patterns are different in immunogenicity.…”