Natural variation in the parameters of innate immune cells is preferentially driven by genetic factors

Abstract

The quantification and characterization of circulating immune cells provide key indicators of human health and disease. To identify the relative effects of environmental and genetic factors on variation in the parameters of innate and adaptive immune cells in homeostatic conditions, we combined standardized flow cytometry of blood leukocytes and genome-wide DNA genotyping of 1,000 healthy, unrelated people of Western European ancestry. We found that smoking, together with age, sex and latent infection with cytomegalovirus, were the main non-genetic factors that affected variation in parameters of human immune cells. Genome-wide association studies of 166 immunophenotypes identified 15 loci that showed enrichment for disease-associated variants. Finally, we demonstrated that the parameters of innate cells were more strongly controlled by genetic variation than were those of adaptive cells, which were driven by mainly environmental exposure. Our data establish a resource that will generate new hypotheses in immunology and highlight the role of innate immunity in susceptibility to common autoimmune diseases.

Milieu intérieur: Defining the boundaries of a healthy immune response for improved vaccination strategies

“…From analysis of the Milieu Interieur cohort we recently identified both genetic and non-genetic determinants that contribute to variance within circulating immune cell populations. 7 As immune cells are the major targets for most vaccines it is important to understand how and why they may differ between individuals. Leveraging the 1,000 well-defined healthy donors and the associated metadata, we identified a significant impact of age, sex and latent cytomegalovirus (CMV) infection on numbers of adaptive immune cells such as T and B cells.…”

“…Leveraging the 1,000 well-defined healthy donors and the associated metadata, we identified a significant impact of age, sex and latent cytomegalovirus (CMV) infection on numbers of adaptive immune cells such as T and B cells. 7 These are the immune cells whose differentiation into long-lived memory cells is the classical hallmark of successful vaccination. Taking advantage of our age-balanced cohort we showed that naïve CD8 + T cells decrease more than twice as rapidly with age as compared to naïve CD4 + T cells (3.5% and 1.5% per year, respectively) showing how age may significantly impact vaccines that target these cellular populations.…”

“…Taking advantage of our age-balanced cohort we showed that naïve CD8 + T cells decrease more than twice as rapidly with age as compared to naïve CD4 + T cells (3.5% and 1.5% per year, respectively) showing how age may significantly impact vaccines that target these cellular populations. 7 CMV latent infection was also revealed to have a major impact on the differentiation status of T cell subsets and was associated with a 12- and 4.5-times higher number of CD4 + and CD8 + T effector memory (TEM) and T effector memory RA (TEMRA) cells. 7 Another strong environmental or lifestyle effect was active smoking, which showed a significant positive effect on the number of circulating leukocytes, and particularly in the number of circulating regulatory T cells.…”

“…7 CMV latent infection was also revealed to have a major impact on the differentiation status of T cell subsets and was associated with a 12- and 4.5-times higher number of CD4 + and CD8 + T effector memory (TEM) and T effector memory RA (TEMRA) cells. 7 Another strong environmental or lifestyle effect was active smoking, which showed a significant positive effect on the number of circulating leukocytes, and particularly in the number of circulating regulatory T cells. Interestingly, genetic effects on circulating leukocytes were more preferentially identified in innate immune cell populations as compared to adaptive cells.…”

“…In total 25% of the measured cellular immunophenotypes showed a genome-wide significant association (p < 1 × 10 −10 ), and of those phenotypes, 80% were innate immune cell-specific. 7 This may reflect the shorter half-life of innate cells as compared to adaptive cells, resulting in environmental effects having a stronger relative influence on these cells as compared to potential genetic determinants. Extrapolating from these results for precision vaccination strategies, we could propose that adjuvant selection should consider genetic variability as it targets innate immune cells, and antigen selection, which is more relevant for adaptive responses should include factors such as age, CMV serostatus and smoking.…”