An immune clock of human pregnancy

Nima Aghaeepour, Edward A. Ganio, David Mcilwain, Amy S. Tsai, Martha Tingle, Sofie Van Gassen, Dyani K. Gaudilliere, Quentin Baca, Leslie McNeil, Robin Okada, Mohammad S. Ghaemi, David Furman, Ronald J. Wong, Virginia D. Winn, Maurice L. Druzin, Yaser Y. El-Sayed, Cecele Quaintance, Ronald Gibbs, Gary L. Darmstadt, Gary M. Shaw, David K. Stevenson, Robert Tibshirani, Garry P. Nolan, David B. Lewis, Martin S. Angst, Brice Gaudilliere

The maintenance of pregnancy relies on finely tuned immune adaptations. We demonstrate that these adaptations are precisely timed, reflecting an immune clock of pregnancy in women delivering at term. Using mass cytometry, the abundance and functional responses of all major immune cell subsets were quantified in serial blood samples collected throughout pregnancy. Cell signaling-based Elastic Net, a regularized regression method adapted from the elastic net algorithm, was developed to infer and prospectively validate a predictive model of interrelated immune events that accurately captures the chronology of pregnancy. Model components highlighted existing knowledge and revealed previously unreported biology, including a critical role for the interleukin-2-dependent STAT5ab signaling pathway in modulating T cell function during pregnancy. These findings unravel the precise timing of immunological events occurring during a term pregnancy and provide the analytical framework to identify immunological deviations implicated in pregnancy-related pathologies.