What is it about?
Pregnancy is remarkable in that mothers tolerate the developing fetus expressing immunologically foreign paternal antigens. These foreign antigens stimulate rejection in other contexts, such as organ transplantation. Investigating how fetal tolerance is maintained holds exciting potential for identifying what causes pregnancy disorders including preeclampsia, miscarriage, stillbirth, and preterm delivery, each increasingly linked to fetal intolerance. Similar fetal tolerance mechanisms promote optimal pregnancy outcomes in animals, including mice. This paper demonstrates the importance of a special type of maternal CD4 T cell with immune suppressive function during pregnancy. Mice lacking these suppressive cells do not easily become pregnant. When pregnancy does occur, these mice are susceptible to fetal loss with fractured tolerance shown by increased harmful activated T cells.
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Why is it important?
Women with inflammatory bowel disease and other inflammatory disorders often have difficulty getting pregnant or are at increased risk of pregnancy complications. We previously identified a subset of CD4 T cells important for suppressing harmful inflammation in the intestine stimulated by microbes. These cells were particularly reduced in biopsy specimens of women with Crohn's disease, one of two types of human inflammatory bowel disease. This paper extends these findings to show these same suppressive CD4 T cells also promote pregnancy by helping the immune system of expecting mothers immunologically tolerate the developing fetus during pregnancy.
Perspectives
I am a pediatrician that focuses primarily on discovery research to better understand why children get sick and to find ways to prevent illness. Pregnancy complications such as prematurity are consistently the leading cause of under age 5 mortality in children. We don't have effective cures for most pregnancy complications because we don't fully understand how pregnancy works in the first place. This includes basic questions including why mothers do not reject their children during pregnancy. Several years ago, my laboratory developed a backdoor way to study this very complex problem. We reasoned that the cells and mechanisms allow mothers to tolerate the baby would be shared by how individuals tolerate commensal microbes that live in our intestine and other mucosal tissues at very high levels. By studying the immune cells stimulated by commensal microbes in the intestine, we identified new suppressive properties for CD4 T cells that express the transcription factor, Kruppel-like factor 2 (or abbreviated KLF2). These KLF2 expressing CD4 T cells were important for protecting mice against intestinal inflammation driven by commensal microbes. KLF2 expressing CD4 T cells were also selectively reduced in intestinal biopsy specimens from individuals with Crohn's disease, a type of human inflammatory bowel disease linked with intolerance of commensal microbes. While there is still alot we do not understand about what causes inflammatory bowel disease and how pregnancy works, this paper demonstrating these same KLF2 CD4 T cells required for protecting against intestinal inflammation also helps promote fertility and optimal pregnancy outcomes provides important new clues for how these processes are immunologically linked.
Sing Sing Way
Cincinnati Children's Hospital Medical Center
Read the Original
This page is a summary of: Maternal Krüppel-like factor 2 (KLF2)+ CD4 T cells promote fertility and fetal tolerance, Proceedings of the National Academy of Sciences, March 2026, Proceedings of the National Academy of Sciences,
DOI: 10.1073/pnas.2519393123.
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