In vitroneutralization of tumor necrosis factor-α duringChlamydia pneumoniaeinfection impairs dendritic cells maturation/function and increases chlamydial progeny

Abstract

Dendritic cells (DCs) produce tumor necrosis factor (TNF)-alpha upon infection and contribute in various ways to defense against pathogenic agents. Several biological agents have been designed to inhibit TNF-alpha activity. However, the use of these inhibitors has been associated with an increased rate of certain opportunistic infections. To study the effect of TNF-alpha inhibition, human monocyte-derived DCs were infected with Chlamydia pneumoniae. TNF-alpha was neutralized by adalimumab, a human anti-TNF-alpha monoclonal antibody. Chlamydiae induced the maturation of DC as determined by flow cytometry and quantitative real-time PCR. However, DC maturation was impaired in the presence of adalimumab. Moreover, neutralization of TNF-alpha resulted in a significant increase of infectious progeny, 16S rRNA gene copy number and development of larger inclusions consisting of different stages of chlamydial development. Additionally, chlamydial infection induced secretion of cytokines/chemokines, which were downregulated by adalimumab treatment. Our data reveal an indirect effect on maturation of DC by C. pneumoniae and that maturation is crucial for the restriction of chlamydial development. The results also demonstrate an increase in infectious progeny after TNF-alpha inhibition, suggesting a contribution of TNF-alpha produced by DCs to chlamydial growth arrest. These data suggest a possible mechanism by which TNF-alpha inhibition enhances the risk of intracellular infections.

Invariant Natural Killer T Cells Promote T Cell Immunity by Modulating the Function of Lung Dendritic Cells during Chlamydia pneumoniae Infection

“…The WT-LDC recipients had higher levels than the KO-LDC recipients of the cytokines that induce type-1 immunity. Of note, our results showed an enhanced production of TNF-α in the lungs of mice receiving WT-LDCs compared to the mice that received KO-LDCs or PBS; this is in line with the finding that TNF-α inhibits Cpn growth [29]. Furthermore, we analyzed both CD4 and CD8 T-cell responses.…”

Dendritic Cells from Aged Subjects Display Enhanced Inflammatory Responses toChlamydophila pneumoniae

“…In addition, increased TNF-secretion by the DCs from aged subjects also favors Th1 responses. However, TNF secretion in response to CPn also inhibits the growth of the bacteria in DCs and regulates inflammation via induction of indoleamine 2,3-dioxygenase (IDO) [34]. The induction of IDO in DCs is a mechanism to prevent replication or persistence of CPn infection but since the present study was performed using UV inactivated CPn, we did not analyze the expression of IDO.…”

Chlamydia muridarumT-Cell Antigens Formulated with the Adjuvant DDA/TDB Induce Immunity against Infection That Correlates with a High Frequency of Gamma Interferon (IFN-γ)/Tumor Necrosis Factor Alpha and IFN-γ/Interleukin-17 Double-Positive CD4+T Cells

“…Recently, a number of reports dealing with various disease targets in different animal models have demonstrated a correlation between protection and high-quality T cells that coexpress multiple cytokines (10,46). TNF is another effector cytokine produced by Th1 cells that can mediate control of intracellular infection, including that due to Chlamydia (23,30,35). In the present study, we assessed antigen-specific IFN-␥-and TNF-␣-producing CD4 ϩ T cells in vaccinated mice.…”