Human Female Genital Tract Infection by the Obligate Intracellular Bacterium <em>Chlamydia trachomatis</em> Elicits Robust Type 2 Immunity

<div><p>While <i>Chlamydia trachomatis</i> infections are frequently asymptomatic, mechanisms that regulate host response to this intracellular Gram-negative bacterium remain undefined. This investigation thus used peripheral blood mononuclear cells and endometrial tissue from women with or without <i>Chlamydia</i> genital tract infection to better define this response. Initial genome-wide microarray analysis revealed highly elevated expression of matrix metalloproteinase 10 and other molecules characteristic of Type 2 immunity (e.g., fibrosis and wound repair) in <i>Chlamydia</i>-infected tissue. This result was corroborated in flow cytometry and immunohistochemistry studies that showed extant upper genital tract <i>Chlamydia</i> infection was associated with increased co-expression of CD200 receptor and CD206 (markers of alternative macrophage activation) by endometrial macrophages as well as increased expression of GATA-3 (the transcription factor regulating T_H2 differentiation) by endometrial CD4⁺ T cells. Also among women with genital tract <i>Chlamydia</i> infection, peripheral CD3⁺ CD4⁺ and CD3⁺ CD4^- cells that proliferated in response to <i>ex vivo</i> stimulation with inactivated chlamydial antigen secreted significantly more interleukin (IL)-4 than tumor necrosis factor, interferon-γ, or IL-17; findings that repeated in T cells isolated from these same women 1 and 4 months after infection had been eradicated. Our results thus newly reveal that genital infection by an obligate intracellular bacterium induces polarization towards Type 2 immunity, including <i>Chlamydia</i>-specific T_H2 development. Based on these findings, we now speculate that Type 2 immunity was selected by evolution as the host response to <i>C. trachomatis</i> in the human female genital tract to control infection and minimize immunopathological damage to vital reproductive structures.</p>