The Interplay Between Loneliness, Cortisol, and NK Cell Function: The Role of Cortisol in NK Cell Dysfunction

Authors

• Abhinav Saurabh, National Heart, Lung, and Blood Institute, Bethesda, MD
• Yvonne Baumer, Macon & Joan Brock Virginia Health Sciences at Old Dominion University
• Laurel G. Mendelsohn, National Heart, Lung, and Blood Institute, Bethesda, MD
• Elizabeth M. Aquino Peterson, National Heart, Lung, and Blood Institute, Bethesda, MD
• Dana Sadler, National Heart, Lung, and Blood Institute, Bethesda, MD
• Shirley J. Lopez De Leon, National Heart, Lung, and Blood Institute, Bethesda, MD
• Ayushi Dave, National Heart, Lung, and Blood Institute, Bethesda, MD
• Andrew S. Baez, National Heart, Lung, and Blood Institute, Bethesda, MD
• Lola R. Ortiz-Whittingham, National Heart, Lung, and Blood Institute, Bethesda, MD
• Mario A. Pita, National Heart, Lung, and Blood Institute, Bethesda, MD
• Manuel A. Cintron, National Heart, Lung, and Blood Institute, Bethesda, MD
• Hannatu A. Tarfa, National Heart, Lung, and Blood Institute, Bethesda MD
• Sandy T. Reynolds, National Heart, Lung, and Blood Institute, Bethesda, MD
• Shelby R. Hicks, National Heart, Lung, and Blood Institute, Bethesda, MD
• Sonal Sharda, National Heart, Lung, and Blood Institute, Bethesda, MD
• J. Eleanor Seo, National Heart, Lung, and Blood Institute, Bethesda, MD
• Maria Lopez-Ocasio, National Heart, Lung, and Blood Institute, Bethesda, MD
• Pradeep K. Dagur, National Heart, Lung, and Blood Institute, Bethesda, MD
• Skyler A. Kuhn, National Institutes of Health
• Neelam R. Redekar, National Institutes of Health
• James F. Troendle, National Heart, Lung, and Blood Institute, Bethesda, MD
• Ayanna L. Wells, National Heart, Lung, and Blood Institute, Bethesda, MD
• Marie Marah, National Heart, Lung, and Blood Institute, Bethesda, MD
• Katherine J. Tolentino, National Heart, Lung, and Blood Institute, Bethesda, MD
• Michael J. Corley, University of California
• Alika K. Maunakea, University of Hawai'i at Manoa
• Lynnette K. Nieman, National Institutes of Health
• Marcus R. Andrews, National Institutes of Health
• Tiffany M. Powell-Wiley, Macon & Joan Brock Virginia Health Sciences at Old Dominion UniversityFollow

ORCID

0000-0001-7400-0773 (Baumer), 0000-0001-9488-4131 (Powell-Wiley)

Document Type

Article

Publication Date

2026

DOI

10.1016/j.psyneuen.2026.107870

Publication Title

Psychoneuroendocrinology

Volume

189

Pages

107870

Abstract

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.

Rights

© 2026 The Authors.

This is an open access article under the Creative Commons Attribution 4.0 International (CC BY 4.0) License.

Data Availability

Article states: "Data presented in this study are available from the corresponding author upon reasonable request and will be uploaded to FigShare. RNA sequencing data were uploaded to NCBI Gene Expression Omnibus (Geo, GSE278321)."

Original Publication Citation

Saurabh, A., Baumer, Y., Mendelsohn, L. G., Peterson, E. M. A., Sandler, D., De Leon, S. J. L., Dave, A., Baez, A. S., Ortiz-Whittingham, L. R., Pita, M. A., Cintron, M. A., Tarfa, H. A., Reynolds, S. T., Hicks, S. R., Sharda, S., Seo, J. E., Lopez-Ocasio, M., Dagur, P. K., Kuhn, S. A.,…Powell-Wiley, T. M. (2026). The interplay between loneliness, cortisol, and NK cell function: The role of cortisol in NK cell dysfunction. Psychoneuroendocrinology, 189, Article 107870. https://doi.org/10.1016/j.psyneuen.2026.107870

Repository Citation

Saurabh, A., Baumer, Y., Mendelsohn, L. G., Peterson, E. M. A., Sandler, D., De Leon, S. J. L., Dave, A., Baez, A. S., Ortiz-Whittingham, L. R., Pita, M. A., Cintron, M. A., Tarfa, H. A., Reynolds, S. T., Hicks, S. R., Sharda, S., Seo, J. E., Lopez-Ocasio, M., Dagur, P. K., Kuhn, S. A.,…Powell-Wiley, T. M. (2026). The interplay between loneliness, cortisol, and NK cell function: The role of cortisol in NK cell dysfunction. Psychoneuroendocrinology, 189, Article 107870. https://doi.org/10.1016/j.psyneuen.2026.107870