The Predominant CD4⁺Th1 Cytokine Elicited to Chlamydia trachomatis Infection in Women Is Tumor Necrosis Factor Alpha and Not Interferon Gamma

Abstract

infection is the most prevalent bacterial sexually transmitted infection and can cause significant reproductive morbidity in women. There is insufficient knowledge of -specific immune responses in humans, which could be important in guiding vaccine development efforts. In contrast, murine models have clearly demonstrated the essential role of T helper type 1 (Th1) cells, especially interferon gamma (IFN-γ)-producing CD4 T cells, in protective immunity to chlamydia. To determine the frequency and magnitude of Th1 cytokine responses elicited to infection in humans, we stimulated peripheral blood mononuclear cells from 90 chlamydia-infected women with elementary bodies, Pgp3, and major outer membrane protein and measured IFN-γ-, tumor necrosis factor alpha (TNF-α)-, and interleukin-2 (IL-2)-producing CD4 and CD8 T-cell responses using intracellular cytokine staining. The majority of chlamydia-infected women elicited CD4 TNF-α responses, with frequency and magnitude varying significantly depending on the antigen used. CD4 IFN-γ and IL-2 responses occurred infrequently, as did production of any of the three cytokines by CD8 T cells. About one-third of TNF-α-producing CD4 T cells coproduced IFN-γ or IL-2. In summary, the predominant Th1 cytokine response elicited to infection in women was a CD4 TNF-α response, not CD4 IFN-γ, and a subset of the CD4 TNF-α-positive cells produced a second Th1 cytokine.

Stimulated peripheral blood mononuclear cells from chlamydia-infected women release predominantly Th1-polarizing cytokines

“…IFN-γ levels were highest when stimulated with EB, compared to Pgp3, which suggests that cytokine levels are related, in part, to antigen specificity (more antigens are present on the EB surface compared to the single recombinant antigen Pgp3). Given our previous finding that TNF-α, not IFN-γ, was the predominant cytokine produced by stimulated CD4 + T-cells [12], our current study findings suggest that in some Ct-infected individuals, there may be a significant contribution by other cell types to IFN-γ production, possibly natural killer (NK) cells. This hypothesis is further supported by a prior study demonstrating that Ct EB-stimulated PBMCs had high levels of IFN-γ production by NK cells [13].…”

“…In this study, we evaluated cytokines in CT-infected women at an enrollment visit, which was part an ongoing longitudinal study that has been previously described [12]. Briefly, females ≥16 years of age returning to a STD clinic for treatment of a positive screening Ct nucleic acid amplification test were enrolled.…”

“…We previously showed in a cohort of Ct-infected women that TNF-a is the predominant Th1 cytokine produced by peripheral CD4 + T-cells from chlamydia-infected women, not IFN-γ, with approximately one third of TNF-γ-positive T-cells co-expressing either IFN-γ or IL-2 [12]. Surprisingly, IFN-γ responses were infrequent in that study, though our analysis was limited to CD4 + and CD8 + T-cells and only evaluated the Th1 cytokines IFN-γ, TNF-α, and IL-2 by intracellular cytokine staining.…”

An Adaptive Chlamydia trachomatis-Specific IFN-γ-Producing CD4+ T Cell Response Is Associated With Protection Against Chlamydia Reinfection in Women

“…This study evaluated 135 women from the study cohort described in our previous study ( 18 ). Briefly, females ≥16 years of age presenting to the Jefferson County Department of Health (JCDH) STD clinic for treatment of a recent positive screening CT NAAT (Hologic Aptima Combo 2 [AC2]; Hologic, Inc., Marlborough, MA) were invited to participate in a study on immune responses to CT infection.…”

“…We previously used ICS to demonstrate that the majority of CT-infected women mounted a CD4 + TNF-α response before treatment, and CD4 + IFN-γ T cell responses were infrequent and, in general, of low magnitude at that time point; we also found heterogeneous T cell responses based on different CT antigens used in the stimulation ( 18 ). Our current study builds on this initial work by investigating changes in CT-specific T cell responses from the time of treatment to follow-up to better understand the adaptive immune response to CT infection and to evaluate whether specific immune responses are associated with lower rates of CT reinfection at follow-up.…”