4 research outputs found
Probing Natural Killer Cell Education by Ly49 Receptor Expression Analysis and Computational Modelling in Single MHC Class I Mice
Murine natural killer (NK) cells express inhibitory Ly49 receptors for MHC class I molecules, which allows for “missing self” recognition of cells that downregulate MHC class I expression. During murine NK cell development, host MHC class I molecules impose an “educating impact” on the NK cell pool. As a result, mice with different MHC class I expression display different frequency distributions of Ly49 receptor combinations on NK cells. Two models have been put forward to explain this impact. The two-step selection model proposes a stochastic Ly49 receptor expression followed by selection for NK cells expressing appropriate receptor combinations. The sequential model, on the other hand, proposes that each NK cell sequentially expresses Ly49 receptors until an interaction of sufficient magnitude with self-class I MHC is reached for the NK cell to mature. With the aim to clarify which one of these models is most likely to reflect the actual biological process, we simulated the two educational schemes by mathematical modelling, and fitted the results to Ly49 expression patterns, which were analyzed in mice expressing single MHC class I molecules. Our results favour the two-step selection model over the sequential model. Furthermore, the MHC class I environment favoured maturation of NK cells expressing one or a few self receptors, suggesting a possible step of positive selection in NK cell education. Based on the predicted Ly49 binding preferences revealed by the model, we also propose, that Ly49 receptors are more promiscuous than previously thought in their interactions with MHC class I molecules, which was supported by functional studies of NK cell subsets expressing individual Ly49 receptors
BCR CDR3 length distributions differ between blood and spleen and between old and young patients, and TCR distributions can be used to detect myelodysplastic syndrome
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Defective Signaling in the JAK-STAT Pathway Tracks with Chronic Inflammation and Cardiovascular Risk in Aging Humans
Chronic inflammation, a decline in immune responsiveness, and reduced cardiovascular function are all associated with aging, but the relationships among these phenomena remain unclear. Here, we longitudinally profiled a total of 84 signaling conditions in 91 young and older adults and observed an age-related reduction in cytokine responsiveness within four immune cell lineages, most prominently T cells. The phenotype can be partially explained by elevated baseline levels of phosphorylated STAT (pSTAT) proteins and a different response capacity of naive versus memory T cell subsets to interleukin 6 (IL-6), interferon α (IFN-α), and, to a lesser extent, IL-21 and IFN-γ. Baseline pSTAT levels tracked with circulating levels of C-reactive protein (CRP), and we derived a cytokine response score that negatively correlates with measures of cardiovascular disease, specifically diastolic dysfunction and atherosclerotic burden, outperforming CRP. Thus, we identified an immunological link between inflammation, decreased cell responsiveness in the JAK-STAT pathway, and cardiovascular aging. Targeting chronic inflammation may ameliorate this deficiency in cellular responsiveness and improve cardiovascular function