Immune cell composition varies by age, sex and exposure to social adversity in free-ranging Rhesus Macaques

Abstract

Increasing age is associated with dysregulated immune function and increased inflammation-patterns that are also observed in individuals exposed to chronic social adversity. Yet we still know little about how social adversity impacts the immune system and how it might promote age-related diseases. Here, we investigated how immune cell diversity varied with age, sex and social adversity (operationalized as low social status) in free-ranging rhesus macaques. We found age-related signatures of immunosenescence, including lower proportions of CD20 + B cells, CD20 + /CD3 + ratio, and CD4 + /CD8 + T cell ratio - all signs of diminished antibody production. Age was associated with higher proportions of CD3 + /CD8 + Cytotoxic T cells, CD16 + /CD3- Natural Killer cells, CD3 + /CD4 + /CD25 + and CD3 + /CD8 + /CD25 + T cells, and CD14 + /CD16 + /HLA-DR + intermediate monocytes, and lower levels of CD14 + /CD16-/HLA-DR + classical monocytes, indicating greater amounts of inflammation and immune dysregulation. We also found a sex-dependent effect of exposure to social adversity (i.e., low social status). High-status males, relative to females, had higher CD20 + /CD3 + ratios and CD16 + /CD3 Natural Killer cell proportions, and lower proportions of CD8 + Cytotoxic T cells. Further, low-status females had higher proportions of cytotoxic T cells than high-status females, while the opposite was observed in males. High-status males had higher CD20 + /CD3 + ratios than low-status males. Together, our study identifies the strong age and sex-dependent effects of social adversity on immune cell proportions in a human-relevant primate model. Thus, these results provide novel insights into the combined effects of demography and social adversity on immunity and their potential contribution to age-related diseases in humans and other animals.

Keywords: Age; Immunosenescence; Inflammation; Sex-differences; Social adversity.

Fig. 1

Sample collection and demographics. A) We collected 369 whole blood samples from 230 unique individuals across three years, and quantified immune cell proportions using flow cytometry. B) The dataset was roughly balanced between males and females and captured the entire natural lifespan of macaques in this population. C) We calculated social status by assigning dominance ranks to 250 samples using observational data collected in the year before each sample was collected. Animals were assigned to one of three dominance ranks: high, medium, and low. The social status dataset is a subset of the original age dataset because behavioral data were not available for all study animals (i.e., it is not collected for infants and juveniles). D) PC1 of immune cell compositions is significantly associated with age (β_PC1 = 0.14, FDR = 7.2 × 10^–18). E) The T cell compartment is positively associated with PC1 (and thus age), while the B cell compartment is negatively associated with PC1 of immune cell composition

Fig. 2

Age-associated differences in adaptive immune cell proportions. A) CD20 + B cells (β_CD20 = −0.83 ± 0.09, FDR = 1.3 × 10^–16) proportions and B) CD20 + /CD3 + ratio (β_CD20:CD3 = −0.04 ± 0.004, FDR = 4.9 × 10^–15) are lower in older individuals. C) CD8 + Cytotoxic T cells (β_CD8 = 0.60 ± 0.07, FDR = 3.2 × 10^–14) are higher in older individuals, while the D) CD4 + /CD8 + T cell ratio (β_CD4:CD8 = −0.06 ± 0.008, FDR = 4.3 × 10^–14) is lower in older individuals. E) CD3 + CD4 + CD25 + T cells (β = 0.16 ± 0.02, FDR = 3.6 × 10^–10) and F) CD3 + CD8 + CD25 + T cells are higher in older individuals compared to younger individuals (β = 0.03 ± 0.005, FDR = 1.8 × 10^–6), possibly because of higher baseline levels of inflammation (i.e., inflammaging)

Fig. 3

Age is associated with variation in innate immune cell proportions. A) CD14 + /CD16-/HLADR + Classical monocytes (β_CD14++  = −0.31 ± 0.16, FDR = 0.07) are lower and B) CD14 + /CD16 + /HLADR + intermediate monocytes (β_CD14+CD16+  = 0.21 ± 0.09, FDR = 0.04) are higher in older individuals, while C) CD16 + NK cells (β_NK = 0.17 ± 0.07, FDR = 0.03) are higher in older individuals

Fig. 4

Sex and social status interact to impact immune cell proportions. A) PC1 (31% of the variation in the dataset, β_{PC1-sex*status} = −1.7, FDR = 0.03) recapitulates the interaction between sex and social status. B) Interaction in the CD20 + /CD3 + ratio (β_{CD20/CD3 ratio-sex*status} = −0.25 ± 0.05, FDR = 0.06) shows that this ratio is higher with higher social status in males while it is lower with higher social status in females; within-sex analysis show that high social status males have a significantly higher ratio than low social status males (β_{CD20/CD3 ratio-males/status} = −1.3 ± 0.06, p = 0.04). C) CD8 + Cytotoxic T cells show an interaction (β_{CD8-sex*status} = 8.3 ± 2.94, FDR = 0.04) where this cell type is higher in lower social status in males, while it is higher in high social status females. Within-sex analysis of CD8 + T cells showed low social status males had significantly higher proportions of this cell type than did high social status males (β_{CD8-males/status} = 4 ± 1.8, p = 0.03), while the opposite effect was observed in females (β_{CD8-females/status} = −4.8 ± 2.1, p = 0.03). D) Interaction in the proportion of NK Cells (β_{NK-sex*status} = −7.9 ± 3.2, FDR = 0.05), with high social status males showing higher proportions, while high social status females show lower proportions