ESC Congress 2026 Abstract · Oct 26, 2026
Cortisol impairs NK cells in a loneliness-dependent manner as a potential contributor to impaired immunity and increased cardiovascular disease risk
By Powell-Wiley T, Saurabh A, Mendelsohn L et al.
Background/Introduction: Chronic stress accelerates cardiovascular disease (CVD), which disproportionally impacts African American (AA) women. Stress is biologically embodied through mechanisms such as cortisol-mediated signaling and the distribution and function of natural killer (NK) cells. However, potential connections between psychosocial stressors, cortisol, and NK cells are largely understudied. Purpose: To determine how chronic stress and cortisol may impact innate immunity, which plays an integral part in cardiovascular diseases. Methods: 186 AA women were recruited in the Step It Up Community-Engaged, Digital Health Physical Activity Intervention. At baseline, NK cells and subsets (cytotoxic and proliferative) in peripheral blood were measured by flow cytometry. Psychosocial stressors (depression, chronic stress, social isolation, and loneliness) were determined using validated questionnaires. Fasting plasma cortisol levels at 8-9am were measured by ELISA. Multivariable linear regression and moderation analyses were performed. All models were adjusted for age, SES, and CV risk factors (e.g. LDL-c, Diabetes, Blood pressure), daily step count, diet, and inflammatory comorbidities. In vitro NK cell receptor-mediated degranulation and cytokine production were measured using flow cytometry after exposure to the K562 target cell line, before and after exposure to cortisol at 300 nmol/L. Results: Step It Up participants were AA women (mean age 57 +/- 12 years, mean BMI 36.3 +/- 7 kg/m^2, at intermediate risk for CVD). Of the psychosocial measures, only loneliness and chronic stress were negatively associated with overall NK cell proportions (b=-0.16, p=0.04 and b=-0.17, p=0.02, respectively). Cortisol was negatively associated with the proportion of proliferative NK cells (b=-0.21, p=0.006). No psychosocial stress measures associated with cortisol. Testing psychosocial factors as moderators, we found that loneliness modified the association between cortisol and proliferative NK cells (p=0.01 for cortisol*loneliness interaction, Figure). Testing the hypothesis that cortisol may impact NK cell function in vitro, we found that 24-hour cortisol exposure, when compared to untreated controls, reduced NK cell degranulation under baseline and activating conditions (8.4% vs 4.9% and 42.4% vs 37.6% CD107a+NK cells), while intracellular IFNg and TNFa expression levels were significantly reduced only under activating conditions. Additionally, cortisol upregulated PD-1 expression on NK cells (p = 0.01) in a FABP4-dependent manner. Lastly, a FABP4 inhibitor was able to prevent cortisol-induced reduction of NK cell degranulation. Conclusion: Increasing cortisol levels, particularly in individuals with higher levels of self-reported loneliness, may reduce NK cell numbers and function in a PD-1/FABP4-dependent manner, leading to impaired immunity, which in turn likely contributes to increased CVD risk.Graphical Abstract