Innate immune profiling reveals a specific reduction of CD57+CD62L+CD161+ NK cells in CMV-positive males with hypertension

Background Innate immune dysregulation is increasingly recognized as a pivotal contributor to hypertension pathogenesis. However, the role of natural killer (NK) cells, a key innate lymphocyte population, remains poorly defined and controversial. Method High-dimensional mass cytometry (CyTOF) was employed to profile the innate compartment of peripheral blood mononuclear cells (PBMCs) from 10 hypertensive and 10 normotensive male subjects. A specifically reduced NK subpopulation (CD57 + CD62L + CD161 + ) was identified and subsequently validated in an independent cohort (10 hypertensive and 6 normotensive male subjects) using full-spectrum flow cytometry. The transcriptional heterogeneity and underlying mechanisms of CD57 + CD62L + CD161 + NK cells were further delineated by single-cell RNA sequencing. Results Innate immune profiling revealed a specific reduction of the CD57 + CD62L + CD161 + NK subpopulation in male hypertensive patients, which was confirmed by flow cytometry. Single-cell RNA sequencing of sorted CD57 + CD62L + CD161 + NK cells uncovered six transcriptionally distinct subsets and identified a pathogenic shift in their composition. Within the overall diminished pool, hypertension drove a specific depletion of the KLRC2 high Adaptive subset while the enhanced cytotoxic, endothelium-interactive FCER1G high Cytotoxic subset was relatively preserved, becoming the dominant population. Mechanistically, the selective loss of the KLRC2 high Adaptive subset was associated with impaired IL-15 signaling, which disrupted the balance between pro-survival ( MCL1 , BCL2 , PIM2 ) and pro-apoptotic ( BCL2L11 , encoding BIM) factors. In contrast, the FCER1G high Cytotoxic subset exhibited relative resistance to this depletion, explaining the observed subset inversion. Conclusion Our study demonstrates that hypertension induces a subset-specific remodeling of the human NK cell repertoire, characterized by a global reduction and pathogenic reshaping of the CD57 + CD62L + CD161 + NK cells. These findings reveal a novel immune mechanism underlying NK cell dysfunction and vascular inflammation in hypertension.