The interplay between loneliness, cortisol, and NK cell function: The role of cortisol in NK cell dysfunction.
Level 3 - non-randomized controlled study
Cross-sectional observational human study with nested functional assays and in vitro mechanistic experiments
PubMed 42105644 · doi:10.1016/j.psyneuen.2026.107870
What was done
In 186 African American women participating in the Step It Up Community-Engaged, Digital Health Physical Activity Intervention study, researchers measured plasma cortisol, natural killer (NK) cell markers, and self-reported chronic stress and loneliness using validated questionnaires. In a subset (n = 24), NK cell degranulation was assessed alongside RNA sequencing to evaluate cytotoxicity-related gene expression. Freshly isolated primary human NK cells were also treated in vitro with cortisol to evaluate its effect on degranulation and the FABP-4/PD-1 pathway.
What was found
Plasma cortisol levels were negatively associated with NK cell proportions, and this relationship was moderated by loneliness (p = 0.011). Among participants reporting higher loneliness, elevated plasma cortisol was associated with lower proliferative NK cell proportions (β = -0.30, p = 0.04). In the subgroup of 24 participants, higher cortisol was associated with reduced NK cell degranulation (β = -0.38, p = 0.03) and suppressed expression of NK cytotoxicity genes. In vitro, cortisol directly inhibited NK cell degranulation (p = 0.006) via FABP-4-dependent upregulation of PD-1 expression (p = 0.01).
Why it matters
These findings outline a specific molecular pathway (the FABP-4/PD-1 axis) linking perceived loneliness and chronic HPA-axis activation to innate immune dysfunction, providing a plausible biological mechanism for how psychosocial stress may exacerbate cardiovascular and immune-related health risks.
Limits
The observational human data are cross-sectional, preventing causal conclusions regarding stress, cortisol, and immune changes in vivo. The human cohort was restricted to African American women, limiting direct generalizability to other populations and sexes. The functional degranulation analysis was conducted in a very small sub-sample (n = 24), and plasma cortisol reflects a single time point rather than integrated diurnal or long-term cortisol exposure.