Concentrations of urinary neopterin, but not suPAR, positively correlate with age in rhesus macaques

This is the final version. Available on open access from Frontiers Media via the DOI in this recordData availability statement: The datasets presented in this study can be found in online repositories. The names of the repository/repositories and accession number(s) can be found below: BioProject, PRJNA715739.Identifying biomarkers of age-related changes in immune system functioning that can be measured non-invasively is a significant step in progressing research on immunosenescence and inflammaging in free-ranging and wild animal populations. In the present study, we aimed to investigate the suitability of two urinary compounds, neopterin and suPAR, as biomarkers of age-related changes in immune activation and inflammation in a free-ranging rhesus macaque (Macaca mulatta) population. We also investigated age-associated variation in gene transcription from blood samples to understand the underlying proximate mechanisms that drive age-related changes in urinary neopterin or suPAR. Neopterin was significantly positively correlated with age, and had a moderate within-individual repeatability, indicating it is applicable as a biomarker of age-related changes. The age-related changes in urinary neopterin are not apparently driven by an age-related increase in the primary signaler of neopterin, IFN-y, but may be driven instead by an age-related increase in both CD14+ and CD14− monocytes. suPAR was not correlated with age, and had low repeatability within-individuals, indicating that it is likely better suited to measure acute inflammation rather than chronic age-related increases in inflammation (i.e., “inflammaging”). Neopterin and suPAR had a correlation of 25%, indicating that they likely often signal different processes, which if disentangled could provide a nuanced picture of immune-system function and inflammation when measured in tandem.National Institutes of Healt

The rhesus macaque as a success story of the Anthropocene

This is the final version. Available on open access from eLife Sciences Publications via the DOI in this recordData availability: No new data was generated for this articleOf all the non-human primate species studied by researchers, the rhesus macaque (Macaca mulatta) is likely the most widely used across biological disciplines. Rhesus macaques have thrived during the Anthropocene and now have the largest natural range of any non-human primate. They are highly social, exhibit marked genetic diversity, and display remarkable niche flexibility (which allows them to live in a range of habitats and survive on a variety of diets). These characteristics mean that rhesus macaques are well-suited for understanding the links between sociality, health and fitness, and also for investigating intra-specific variation, adaptation and other topics in evolutionary ecology.National Institutes of Healt

Identification and selective expansion of functionally superior T cells expressing chimeric antigen receptors

Background: T cells expressing chimeric antigen receptors (CARs) have shown exciting promise in cancer therapy, particularly in the treatment of B-cell malignancies. However, optimization of CAR-T cell production remains a trial-and-error exercise due to a lack of phenotypic benchmarks that are clearly predictive of anti-tumor functionality. A close examination of the dynamic changes experienced by CAR-T cells upon stimulation can improve understanding of CAR–T-cell biology and identify potential points for optimization in the production of highly functional T cells. Methods: Primary human T cells expressing a second-generation, anti-CD19 CAR were systematically examined for changes in phenotypic and functional responses to antigen exposure over time. Multi-color flow cytometry was performed to quantify dynamic changes in CAR-T cell viability, proliferation, as well as expression of various activation and exhaustion markers in response to varied antigen stimulation conditions. Results: Stimulated CAR-T cells consistently bifurcate into two distinct subpopulations, only one of which (CARhi/CD25+) exhibit anti-tumor functions. The use of central memory T cells as the starting population and the resilience—but not antigen density—of antigen-presenting cells used to expand CAR-T cells were identified as critical parameters that augment the production of functionally superior T cells. We further demonstrate that the CARhi/CD25+ subpopulation upregulates PD-1 but is resistant to PD-L1-induced dysfunction. Conclusions: CAR-T cells expanded ex vivo for adoptive T-cell therapy undergo dynamic phenotypic changes during the expansion process and result in two distinct populations with dramatically different functional capacities. Significant and sustained CD25 and CAR expression upregulation is predictive of robust anti-tumor functionality in antigen-stimulated T cells, despite their correlation with persistent PD-1 upregulation. The functionally superior subpopulation can be selectively augmented by careful calibration of antigen stimulation and the enrichment of central memory T-cell type. Electronic supplementary material The online version of this article (doi:10.1186/s12967-015-0519-8) contains supplementary material, which is available to authorized users

Demography and climate influence sex‐specific survival costs of reproduction over 60 years in a free ranging primate population

This is the author accepted manuscript. The final version is available from Wiley via the DOI in this recordData availability statement: Data are available from the Figshare Repository: https://figshare.com/s/f8d328c2101a7ef10c8a (Cooper et al. 2024).The life-history tradeoff between reproduction and survival often results in a discordant timing of peak mortality risk for males and females in seasonally reproducing species. Understanding how this seasonal association between reproductive investment and survival is impacted by individual age, demography, and climate is increasingly important as anthropogenic influence is driving rapid global climate and population structure changes. We investigate how tradeoffs between seasonal reproductive investment and survival have fluctuated in response to observed changes in demography and climate using 60 years of demographic records collected from a free-ranging population of rhesus macaques Macaca mulatta (n = 1919 males, 1609 females). Seasonal mortality rates fluctuated significantly over the 60-year period for both males and females. In males, but not females, age-specific survival was different during periods of low and high reproductive investment, indicating that tradeoffs between reproduction and survival are particularly age-dependent in males. There was no little to no evidence for an effect of sex ratio on survival in either sex. In both sexes, higher population density was associated with lower survival, and this negative effect of density was particularly strong during each sex's period of low reproductive investment. While there was no evidence for an effect of temperature on female survival during periods of low reproductive investment, during periods of high reproductive investment there was a positive association between average daily temperature maximum and female survival. Female survival was higher overall when rainfall was greater, and this positive effect of rainfall on survival was particularly strong for females during periods of low reproductive investment. Conversely, there were no effects of temperature or rainfall on male survival. The results of this study illustrate the considerable ways that climatic and demographic factors can influence sex-specific mortality during each sex's distinct periods of reproductive investment.National Institutes of Health (NIH)National Science Foundation (NSF

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

This is the author accepted manuscript. The final version is available from Springer via the DOI in this recordData availability: The dataset and code to replicate analysis and plots is available at https://github.com/MSROSADO/Flow_cytometry_analysis. Any other materials can be made available upon request to the author.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.National Institutes of Health (NIH)National Science Foundation (NSF)European Research Council (ERC