Maternal tolerance of the semi-allogeneic fetus is accomplished, in part, by the expression of cytokines and other immunoregulatory molecules at the maternal-fetal interface which modulate appropriate placental immunology [1, 2]. The Th1/Th2 paradigm, which assumed that Th2 (anti-inflammatory) cytokines dominate the maternal-fetal interface during most of pregnancy while Th1 (pro-inflammatory) cytokines are suppressed until the approach of parturition , has been recently succeeded by a Th1/Th2/Th17 and regulatory T cell paradigm  that allows for a cytokine milieu during various stages of pregnancy which does not fit the traditional Th1/Th2 model. Clearly, placental immunology is highly complex and temporal, coincident with changes in cell populations and immunomodulation as pregnancy progresses from implantation to onset of labor (reviewed in ).
Tregs and Th17 cells differentiate from a common T helper progenitor cell. TGF-β causes the proliferation of both Treg and Th17 cells [6, 7]. During inflammation, enhanced production of IL-6 inhibits the induction of FoxP3, halting the generation of Tregs, and activates the expression of RORγ, driving the proliferation of Th17 cells . Th17 cells further enhance the inflammatory response by releasing the cytokines IL17, IL-6, TNFα, and IL-22. Thus, IL-6 levels dictate a pro- or anti-inflammatory cellular response and an inverse relationship between Tregs and Th17 cells . Disruption in cytokine expression potentially perturbs the balance in the two cell populations.
Several investigators have correlated increased numbers of activated Treg cells in the periphery and decidua with successful pregnancies, while a reduced number of Tregs accompany failed pregnancies [9–11]. The inflammatory cytokine IL-17, a product of Th17 cells, was found to localize in cytotrophoblast and syncytiotrophoblast cells in the deciduas of unexplained recurrent spontaneous abortions (URSA) and normal early pregnant women, but IL-17 was significantly higher in the URSA group . This finding suggests that Th17 cells may play a role in pregnancy failure.
The complexity of placental immunology confounds the ability to define the causal relationship between aberrant placental immunology and perturbed pregnancy. Importantly, HIV infection in pregnant women has been associated with increased reproductive failure [13, 14], and there is evidence that the virus alters placental cytokine expression, promoting mother-to-child transmission . The need for additional study is apparent; yet, the inability to obtain human tissues at will to conduct these investigations highlights the value of an animal model.
We use the FIV-infected cat model to evaluate parameters of lentivirus-induced placental inflammation. Our previous data suggest a pro-inflammatory placental microenvironment at early pregnancy in the infected cat, based on the ratio of pro- to anti-inflammatory cytokines, expression of IL-6 , and the likely decreased population of Tregs . In the present study we hypothesized that FIV infection in the pregnant cat causes altered placental Treg and Th17 cell population dynamics, allowing placental inflammation that may compromise pregnancy. Placental immunology is distinctly different at early and late stages of pregnancy; therefore, it was important to evaluate the impact of FIV infection in the feline placenta at these two time points. Our first objective was to localize the two cell populations by labeling parallel sections with either FoxP3 or RORγ-specific antibody and comparing both to a parallel specimen immunolabeled with anti-relaxin antibody. As relaxin is produced by trophoblasts, its presence demarcates the maternal-fetal interface. The two cell populations were localized to this region. Our second objective was to quantify the expression of Treg marker FoxP3 and Th17 marker RORγ in placental samples from FIV-infected and control queens at early gestation by immunofluorescence confocal microscopy. FoxP3 expression was significantly reduced in infected tissues while RORγ expression was unaffected. FoxP3 and RORγ were positively correlated in FIV-infected placentas, while in control placentas no correlation occurred. The third objective was to evaluate expression of the key cytokines that drive Treg and Th17 proliferation, TGF-β and IL-6. TGF-β was significantly reduced, and the normal positive correlation in co-expression between the two cytokines was disrupted in infected tissues. Finally, we correlated expression of IL-6 with RORγ. As an enhanced level of IL-6 is indicative of inflammation, its expression should be inversely correlated to Treg function and positively correlated with Th17 function. In control cats the expression of IL-6 and RORγ was positively correlated as predicted, but this relationship was disrupted in infected animals. Collectively, the data suggest that FIV-induced immunopathology may include perturbation of Treg/Th17 cell balance at early pregnancy. This report supports our prior evidence of a virus-induced, pro-inflammatory placental microenvironment at early pregnancy.