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Introduction: Hypertension is a multifactorial process. Activation of the innate immune system and subsequent upregulation of adaptive immunity have been shown to promote hypertension in various mouse models Large scale human population studies examining the composition of the innate and adaptive immune system as it pertains to hypertension are lacking.Hypothesis: The composition of innate and adaptive immune cells are risk factors for increased systolic blood pressure (SBP).Methods: Using cells cryopreserved from the baseline exam, we measured 34 immune cell subsets from participants of the Multi-Ethnic Study of Atherosclerosis (MESA) (mean age 64 years, 53% male), sampled from a case-cohort study of myocardial infarction (n=1,200). SBP was assessed at baseline and at four follow-up exams over the succeeding ten years. Our approach to anti-hypertensive medication use was to add 10mmHG to SBP for treated participants. Associations between immune cell subpopulations and SBP were conducted using linear mixed models, with sampling weights to account for the sampling strategy and robust confidence intervals; immune cells were modeled per standard (SD) deviation higher value. We adjusted for age, sex, race/ethnicity, smoking, exercise, body mass index, education, diabetes, and log- transformed cytomegalovirus levels.Results: After adjustment for potential confounders, 5 of 34 immune cells subsets were significantly associated with mean levels of SBP. For each standard deviation increment higher immune cell proportion, natural killer (NK) cells, defined as CD3-CD56+CD16+, (1.9 mmHG; 95% CI: 0.8-2.9), classic monocytes, defined as CD14++CD16-, (-1.3 mmHG; 95% CI: -2.5 to -0.1) and non-classic monocytes, defined as CD14+CD16++, (1.4 mmHG; 95% CI: 0.3 to 2.6) had the strongest associations with SBP changes over 10-years of follow-up. Sensitivity analyses with principal components analysis were supportive of these findings. After using a Bonferroni corrected threshold to account for for multiple testing only NK remained significant.Conclusions: NK cells, classic monocytes and non-classic monocytes, all components of the innate immune system, were associated with higher levels of SBP over follow-up. The strongest association was with natural killer cells; in agreement with previous studies that showed circulating levels of interferon gamma and tumor necrosis factor alpha, the two main cytokines produced by NK cells, correlate with systolic blood pressure.