Innate Lymphoid Cells Are Required for Endometrial Resistance toChlamydia trachomatisInfection

Abstract

In some women, sexually transmitted Chlamydia trachomatis may ascend to infect the endometrium, leading to pelvic inflammatory disease. To identify endometrial innate immune components that interact with Chlamydia, we introduced C. trachomatis into mouse endometrium via transcervical inoculation and compared the infectious yields in mice with and without immunodeficiency. Live C. trachomatis recovered from vaginal swabs or endometrial tissues peaked on day 3 and then declined in all mice with or without deficiency in adaptive immunity, indicating a critical role for innate immunity in endometrial control of C. trachomatis infection. Additional knockout of interleukin 2 receptor common gamma chain (IL-2Rγc) from adaptive immunity-deficient mice significantly compromised the endometrial innate immunity, demonstrating an important role for innate lymphoid cells (ILCs). Consistently, deficiency in IL-7 receptor alone, a common gamma chain-containing receptor required for ILC development, significantly reduced endometrial innate immunity. Furthermore, mice deficient in RORγt or T-bet became more susceptible to endometrial infection with C. trachomatis, suggesting a role for group 3-like ILCs in endometrial innate immunity. Furthermore, genetic deletion of gamma interferon (IFN-γ) but not IL-22 or antibody-mediated depletion of IFN-γ from adaptive immunity-deficient mice significantly compromised the endometrial innate immunity. Finally, depletion of NK1.1+ cells from adaptive immunity-deficient mice both significantly reduced IFN-γ and increased C. trachomatis burden in the endometrial tissue, confirming that mouse ILCs contribute significantly to endometrial innate immunity via an IFN-γ-dependent effector mechanism. It will be worth investigating whether IFN-γ-producing ILCs also improve endometrial resistance to sexually transmitted C. trachomatis infection in women.

Innate IFN-γ Is Essential for Systemic Chlamydia muridarum Control in Mice, While CD4 T Cell-Dependent IFN-γ Production Is Highly Redundant in the Female Reproductive Tract

“…Our data add to previous findings by showing ex vivo IFN secretion on the surface of CD11b+ NK1.1+ cells, indicating that group 1 ILCs elicit protective function, as least in part, by their production of IFN in the absence of T cells. It should be noted that both IFN-depleted and NK1.1-depleted Rag1-/-mice exhibited slightly longer survival times than Rag2-/-c-/-mice, indicating that additional cellular sources, such as ILC3s, may also produce IFN and confer protection against Chlamydia as shown in the mouse endometrium tissue in a recent study (41). Additionally, other protective mechanisms independent of IFN may be involved in ILC-mediated protection.…”

The Immune Characteristics of the Epididymis and the Immune Pathway of the Epididymitis Caused by Different Pathogens

“…The most important profile of a CT infection is a local immune response. First, the immune cells are recruited to the site of the infection and secrete pro-inflammatory cytokines such as interferon-γ (IFN-γ) ( 108 , 109 ). IFN-γ has a dual function of inhibiting the growth of CT ( 110 ) in mice and inducing Th1 immune responses in CT-infected women ( 111 ).…”

Innate Lymphoid Cells in Response to Intracellular Pathogens: Protection Versus Immunopathology

“…Recent studies addressed the role of ILCs and NK cells in GI and genital tract Chlamydia infection ( Koprivsek et al., 2020 ; Xu et al., 2020 ; Barth et al., 2021 ; He et al., 2021 ; Mercado et al., 2021 ) ( Figure 6 ). A study using a Chlamydia mutant strain, which is unable to maintain long-lasting colonization in the GI tract, demonstrated that IFNγ-producing NK1.1 + ILC3s can protect against colonization of the colon ( Koprivsek et al., 2020 ).…”

“…ILCs were also found to protect against Chlamydia in the genital tract ( Xu et al., 2020 ; Mercado et al., 2021 ). Thus, Rag2 -/- Il2rg -/- mice lacking all ILCs subsets succumbed earlier to genital C. muridarum infection compared to Rag1 -/- mice ( Mercado et al., 2021 ).…”