The interplay between loneliness, cortisol, and NK cell function: The role of cortisol in NK cell dysfunction

Chronic psychosocial stressors contribute to cardiovascular disease (CVD) and related risk factors, particularly in under-resourced communities. Psychosocial stressors activate the hypothalamic-pituitary-adrenal (HPA) axis, leading to sustained cortisol action on immune cells. Natural killer (NK) cells are altered in distribution and function in cardio-metabolic diseases; however, pathways linking cortisol as a marker of chronic stress to NK cell dysfunction remain understudied. We recruited 186 African American women from the Step It Up Community-Engaged, Digital Health Physical Activity Intervention study and collected cortisol, NK cell measures, and psychosocial stress measures using validated questionnaires, including chronic stress and loneliness. Plasma cortisol levels were negatively associated with NK cell proportions, and self-reported levels of loneliness modified this relationship (p = 0.011); among participants with higher loneliness, higher plasma cortisol levels were associated with lower proliferative NK cell proportions (β=-0.30, p = 0.04). In a subset of study participants (n = 24), plasma cortisol levels were directly associated with a loss of NK cell degranulation (β=-0.38, p = 0.03). Using an RNA sequencing dataset, we found that higher plasma cortisol levels were associated with suppressed gene expression related to NK cell cytotoxicity. Finally, in vitro experiments on freshly isolated primary NK cells revealed that cortisol reduces NK cell degranulation (p = 0.006) via FABP-4-induced upregulation of PD-1 expression (p = 0.01). In summary, our study provides evidence that in individuals with higher loneliness, cortisol may alter NK cell distribution and function. Furthermore, cortisol-mediated NK cell dysfunction may be facilitated in a FABP-4/PD-1 dependent manner, leading to impaired innate immune function and, potentially, contributing to worsening CVD risk.