Impact of a Moderate-Intensity Aerobic Exercise Intervention on Systemic and Uterine Natural Killer Cells in Women with Unexplained Recurrent Pregnancy Loss

Aysel Gurbanova¹Amber Lombardi^2,3Denise Habets^2,3Salwan Al-Nasiry⁴Marc Spaanderman^4,5Marien De Jonge¹Tess Meuleman⁵Lotte Wieten^2,3Renate Van Der Molen^1*

• ¹Department of Laboratory Medicine, Laboratory of Medical Immunology, Radboud University Medical Center, Nijmegen, Netherlands
• ²Department of Transplantation Immunology and Tissue Typing, Maastricht University Medical Centre, Maastricht, Netherlands, Netherlands
• ³GROW School for Oncology & Reproduction, Faculty of Health, Medicine and Life Sciences, Maastricht University, Maastricht, Netherlands, Netherlands
• ⁴Department of Obstetrics and Gynecology, Maastricht University Medical Centre, Maastricht, Limburg, Netherlands
• ⁵Department of Obstetrics and Gynaecology, Radboud University Medical Centre, Nijmegen, Netherlands

Recurrent pregnancy loss (RPL) is associated with altered immune phenotypes and functions. It has been proposed that physical exercise might impact the immune system. Therefore, we evaluated the effect of a personalized 3-month moderate-intensity aerobic exercise intervention on the immune system of women with unexplained RPL (uRPL). Given the suggested supportive role of Natural Killer (NK) cells during early pregnancy, we focused on numerical, phenotypic, and functional changes in peripheral NK (pNK) and uterine NK (uNK) cells. Mononuclear cells were isolated from peripheral blood (PB) (n=23) and menstrual blood (MB) (n=22) of women with uRPL. NK cell phenotypes were assessed with comprehensive flow cytometry panels. NK cell function was assessed with degranulation assays and intracellular staining of interferon-γ (IFN-γ), perforin and granzyme-B in a subgroup of women due to lower availability of samples (n=12). Attendance to the exercise intervention was overall 95%, which resulted in effects on the phenotype and function of pNK cells. We found a significant reduction in the median fluorescent intensity of CD161 (464 vs 410, p=0.011), NKp30 (432 vs 376, p=0.018), and NKG2A (886 vs 732, p=0.039) in pNK cells after exercise, while no differences were observed in uNK cells. We also observed decreased percentages of IFN-γ+ pNK cells (49% vs 25.2%, p=0.027) after exercise. Our study shows promising results, suggesting that exercise can impact pNK cell phenotype and function in women with uRPL. Following the changes in pNK phenotype and function suggest a lower pro-inflammatory state post-exercise. Whether these exercise-induced phenotypic and functional changes of pNK cells impact subsequent pregnancies remains to be studied. The study details are available through Home | ClinicalTrials.gov, trial ID: HMOVE