IL-10 Producing B Cells Protect against LPS-Induced Murine Preterm Birth by Promoting PD1- and ICOS-Expressing T Cells

Abstract

B cells and in particular IL-10-secreting B cells emerge as important players in immune balance during pregnancy. We have recently revealed that CD19-deficient (CD19−/−), B cell-specific IL-10-deficient (BIL-10−/−) and B cell-deficient µMT pregnant mice are highly susceptible to LPS-induced preterm birth (PTB). We aimed to analyze the ability of IL-10-secreting cells to protect from PTB and the underlying mechanisms. Wild type (WT), CD19−/−, BIL-10−/− and µMT mice were treated with LPS at gd16 and the cellular immune response was investigated 24 h later. LPS-treated BIL-10−/− dams showed a more pronounced PTB phenotype compared to WT, CD19−/− and µMT females, and increased inflammatory and reduced anti-inflammatory mediator concentrations in the peritoneal cavity and serum. CD19−/−, BIL-10−/− and µMT mice displayed altered immune cell population frequencies in the blood and uterus with lower numbers of IL-10-secreting B cells and T cells. BIL-10−/− mothers presented decreased frequencies of uterine CD4+CD25+Foxp3+ Treg cells. Co-stimulatory molecules are critical for feto-maternal tolerance and IL-10 secretion. We found dysregulated PD-1 expression in peripheral blood and ICOS expression in the uterus of CD19−/−, BIL-10−/− and µMT dams. Our data show that B cell-specific IL-10-signaling is essential for a balanced maternal immune response to an inflammatory stimulant that cannot be hampered without IL-10-secreting B cells.

A Novel Predictive Machine Learning Model Integrating Cytokines in Cervical-Vaginal Mucus Increases the Prediction Rate for Preterm Birth

“…In most previous publications concerning cytokines in cervical-vaginal fluid, the elevated concentrations of IL-10 have been proposed as a protective factor for preterm delivery [ 41 , 42 ], because it belongs to the group of cytokines with anti-inflammatory activity. In our study, the highest concentrations were observed in the high-risk group, which is in agreement with the study by Vogel et al who reported that the elevated IL-10 concentrations could also be associated with an increased risk of preterm delivery (RR 3.1 CI 95% 0.96–9.7) [ 43 ] becoming a response to an inflammatory mechanism that was previously initiated [ 41 ].…”

B Cells Induce Early-Onset Maternal Inflammation to Protect against LPS-Induced Fetal Rejection

“…Alterations in the intricate interplay between the immune system, reproductive tissues and gestational hormones may account for a part of preterm deliveries. Our previous research revealed a reduction of the serum levels of progesterone, a crucial pregnancy hormone known to suppress uterine contractions, 24 h after a LPS challenge in CD19 −/− , BMyD88 −/− and µMT dams, which ultimately delivered [17]. Several hormone functions are mediated by the progesterone induced blocking factor (PIBF).…”

“…In our former work, we found an imbalance between pro-and anti-inflammatory B cells with a decreased frequency of IL-10-secreting Breg cells in women with preterm birth (PTB) [12][13][14]. Further, we showed the importance of functional B-cellspecific MyD88, IL-10 and CD19 signaling in mouse models of inflammation-induced intrauterine fetal death (IUFD) and PTB using intraperitoneal injection of LPS [15][16][17]. We also identified a role of B-cell-specific IL-10, CD19 and MyD88 in the appropriate intrauterine fetal development [18].…”

Preterm birth, a consequence of immune deviation mediated hyperinflammation

“…Moreover, a distinct subset of B cells, known as regulatory B cells (Bregs) which have demonstrated the capacity for interleukin-10 (IL-10) secretion, has garnered attention for its role in placental and fetal growth, implicated in the occurrence of preterm labor [ 78 , 79 ]. Animal studies involving BIL10 deficient mice further support the idea that these mice were more susceptible to preterm labor, accompanied by increased uterine artery resistance [ 80 ]. In conclusion, these findings posited that decreased decidual B cells significantly contribute to the development of spontaneous preterm labor.…”