Chlamydia muridarum Infection Subverts Dendritic Cell Function to Promote Th2 Immunity and Airways Hyperreactivity

Abstract

There is strong epidemiological evidence that Chlamydia infection can lead to exacerbation of asthma. However, the mechanism(s) whereby chlamydial infection, which normally elicits a strong Th type 1 (Th1) immune response, can exacerbate asthma, a disease characterized by dominant Th type 2 (Th2) immune responses, remains unclear. In the present study, we show that Chlamydia muridarum infection of murine bone marrow-derived dendritic cells (BMDC) modulates the phenotype, cytokine secretion profile, and Ag-presenting capability of these BMDC. Chlamydia-infected BMDC express lower levels of CD80 and increased CD86 compared with noninfected BMDC. When infected with Chlamydia, BMDC secrete increased TNF-α, IL-6, IL-10, IL-12, and IL-13. OVA peptide-pulsed infected BMDC induced significant proliferation of transgenic CD4+ DO11.10 (D10) T cells, strongly inhibited IFN-γ secretion by D10 cells, and promoted a Th2 phenotype. Intratracheal transfer of infected, but not control noninfected, OVA peptide-pulsed BMDC to naive BALB/c mice, which had been i.v. infused with naive D10 T cells, resulted in increased levels of IL-10 and IL-13 in bronchoalveolar lavage fluid. Recipients of these infected BMDC showed significant increases in airways resistance and decreased airways compliance compared with mice that had received noninfected BMDC, indicative of the development of airways hyperreactivity. Collectively, these data suggest that Chlamydia infection of DCs allows the pathogen to deviate the induced immune response from a protective Th1 to a nonprotective Th2 response that could permit ongoing chronic infection. In the setting of allergic airways inflammation, this infection may then contribute to exacerbation of the asthmatic phenotype.

Chlamydia pneumoniae-Specific IgE Is Prevalent in Asthma and Is Associated with Disease Severity

“…Further research is required to determine whether these infection-associated mast cells are activated by Cp IgE to produce worsening asthma symptoms. In addition, chamydial infection of dendritic lung cells has been shown to promote overall Th2 immunity and airways hyperreactivity [41], suggesting the possibility that infection might also promote a more general atopic predisposition. Recent experimental evidence indicates that chlamydial lung infection may induce or worsen several hallmarks of asthma including airway inflammation [42], [43], [44], airway hyperresponsiveness [42], [45], mucous hypersecretion [45], [46] and IL-13 production [45].…”

Innate immune responses during respiratory tract infection with a bacterial pathogen induce allergic airway sensitization

“…Previous studies addressing the impact of Chlamydia on allergic airway inflammation in murine models have focused on exacerbation of pre-existing asthma by infecting previously sensitized mice with C. trachomatis or C. muridarum 29, 30. These studies yielded conflicting results; C. trachomatis inhibited airway inflammation 30, but C. muridarum infection was associated with an increase in inflammatory parameters 29.…”

Antigen-Pulsed Bone Marrow–Derived and Pulmonary Dendritic Cells Promote Th2 Cell Responses and Immunopathology in Lungs during the Pathogenesis of Murine Mycoplasma Pneumonia

“…This is in contrast to other studies showing positive effects of adoptive transfer of Ag-pulsed DCs on the host immune response in other bacterial infection models using primary BMDCs or JAWS II murine DC cell lines, such as Helicobacter pylori and Chlamydia muridarum (61, 62) and cancer therapy [reviewed in (63)]. However, DC can exacerbate the severity of respiratory diseases, such as asthma hypersensitivity (64) and airway reactivity associated with Chlamydia muridarum respiratory disease (65). Thus, DC populations can stimulate or support detrimental immune responses involved in inflammatory lesions characteristic of mycoplasma pneumonia, and do not readily help generate beneficial local immune responses that confer resistance to infection.…”