Abstract
Defining the mechanisms of immunity conferred by the combination of antibody and CD4+ T cells is fundamental to designing an efficacious chlamydial vaccine. Using the Chlamydia muridarum genital infection model of mice, which replicates many features of human C. trachomatis infection and avoids the characteristic low virulence of C. trachomatis in the mouse, we previously demonstrated a significant role for antibody in immunity to chlamydial infection. We found that antibody alone was not protective. Instead, protection appeared to be conferred through an undefined antibody-cell interaction. Using gene knockout mice and in vivo cellular depletion methods, our data suggest that antibody-mediated protection is dependent on the activation of an effector cell population in genital tract tissues by CD4+ T cells. Furthermore, the CD4+ T cell-secreted cytokine gamma interferon (IFN-γ) was found to be a key component of the protective antibody response. The protective function of IFN-γ was not related to the immunoglobulin class or to the magnitude of the Chlamydia-specific antibody response or to recruitment of an effector cell population to genital tract tissue. Rather, IFN-γ appears to be necessary for activation of the effector cell population that functions in antibody-mediated chlamydial immunity. Our results confirm the central role of antibody in immunity to chlamydia reinfection and demonstrate a key function for IFN-γ in antibody-mediated protection.
Highlights
Chlamydia trachomatis is an obligate intracellular bacterium responsible for more than 1.4 million genital infections annually in the United States and for approximately 106 million genital infections annually worldwide [1]
Previous studies have shown that antibodymediated protection against genital chlamydia infection is dependent on activation and/or recruitment of an effector cell population to the local genital tract tissues by CD4ϩ T cells
Since the recruitment of possible effector cells for antibody-mediated immunity was not impacted by CD4ϩ T cell depletion, we assessed if CD4ϩ T cells were responsible for the activation of an effector cell population that functioned with antibody to resolve infection
Summary
Chlamydia trachomatis is an obligate intracellular bacterium responsible for more than 1.4 million genital infections annually in the United States and for approximately 106 million genital infections annually worldwide [1]. CD4ϩ T cells appear to be playing a dual role in the protective response against C. muridarum, as they function to resolve primary infection independently of CD8ϩ T cells and antibody [12] and function cooperatively with antibody [5, 6, 12]. Several lines of evidence support the idea of a cooperative function between antibody and CD4ϩ T cells and provide evidence that CD4ϩ T cells are responsible for the recruitment and/or activation of a local effector cell population that functions with antibody to resolve infection. CD4ϩ T cells are known to secrete a variety of proinflammatory cytokines and chemokines that are capable of recruiting and activating other immune cells at the site of infection [4] One such cytokine that is produced in response to chlamydial genital infection is IFN-␥ [4]. Because IFN-␥ is produced by CD4ϩ T cells and is known to activate cell populations that interact with antibody (e.g., macrophages) to kill pathogens, we sought to investigate the role of IFN-␥ in antibody-mediated immunity to genital chlamydia
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