Fetal interventions to diagnose and treat congenital anomalies are growing in popularity but often lead to preterm labor. The possible contribution of the maternal adaptive immune system to post-surgical pregnancy complications has not been explored. We recently showed that fetal intervention in mice increases maternal T cell trafficking into the fetus and hypothesized that this process may also lead to increased maternal T cell recognition of the foreign conceptus and subsequent breakdown in maternal-fetal tolerance. Here, we show that fetal intervention in mice results in accumulation of maternal T cells in the uterus and that these activated cells can produce effector cytokines. In adoptive transfer experiments, maternal T cells specific for a fetal alloantigen proliferate after fetal intervention, escape apoptosis, and become enriched compared to endogenous T cells in the uterus and uterine-draining lymph nodes. Finally, we demonstrate that such activation and accumulation can have a functional consequence: in utero transplantation of hematopoietic cells carrying the fetal alloantigen leads to enhanced demise of semiallogeneic fetuses within a litter. We further show that maternal T cells are necessary for this phenomenon. These results suggest that fetal intervention enhances maternal T cell recognition of the fetus and that T cell activation may be a culprit in post-surgical pregnancy complications. Our results have clinical implications for understanding and preventing complications associated with fetal surgery such as preterm labor.
Background Acute cellular rejection is a major cause of morbidity following lung transplantation. Because regulatory T cells (Treg) limit rejection of solid organs, we hypothesized that donor-reactive Treg increase after transplantation with development of partial tolerance and decrease relative to conventional CD4+ (Tconv) and CD8+ T cells during acute cellular rejection. Methods To test these hypotheses, we prospectively collected 177 peripheral blood mononuclear cell (PBMC) specimens from 39 lung transplant recipients at the time of transplantation and during bronchoscopic assessments for acute cellular rejection. We quantified the proportion of Treg, CD4+ Tconv, and CD8+ T cells proliferating in response to donor-derived, stimulated B cells. We used generalized estimating equation-adjusted regression to compare donor-reactive T cell frequencies with acute cellular rejection pathology. Results An average of 16.5±9.0% of pretransplantation PBMC Treg were donor-reactive, compared with 3.8%±2.9% of CD4+ Tconv and 3.4±2.6% of CD8+ T cells. These values were largely unchanged following transplantation. Donor-reactive CD4+ Tconv and CD8+ T cell frequencies both increased 1.5-fold (95% CI 1.3-1.6, P <0.001 and 95% CI 1.2-1.6, P = 0.007, respectively) during A2-grade rejection compared with no rejection. Surprisingly, donor-reactive Treg frequencies increased by 1.7-fold (95% CI 1.4-1.8, P <0.001). Conclusions Contrary to prediction, overall proportions of donor-reactive Treg are similar before and after transplantation and increase during A2-grade rejection. This suggests how A2 rejection can be self-limiting. The observed increases over high baseline proportions in donor-reactive Treg were insufficient to prevent acute lung allograft rejection.
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