PLCG2 variant p.P522R - associated with healthy aging- may reduce the aging of the human immune system

Abstract Background: Phospholipase C gamma 2 (PLCγ2) is encoded by the PLCG2 gene. A single-nucleotide polymorphism (p.P522R) associates with protection against several dementia subtypes and with increased likelihood of longevity. Cell lines and animal models indicated that p.P522R is a functional hypermorph. We aimed to confirm this in human peripheral immune cells. Methods: We compared effects of p.P522R on immune system function between carriers and non-carriers (aged 59-103y), using in-depth immunophenotyping, functional B-cell and myeloid-cell assays, and in vivo SARS-CoV-2 vaccination. Results: As expected, effects of p.P522R on immune cell function were small. Immune cell numbers in p.P522R carriers better resembled a younger reference cohort than those of non-carriers. Moreover, carriers expressed lower levels of FcεRI on several immune cell subsets and elevated CD33 levels on classical monocytes. Upon B-cell stimulation, PLCγ2 phosphorylation and calcium release were increased in carriers compared to non-carriers. Normalized ROS production in myeloid cells was higher upon PLCγ2-dependent stimulation, but lower upon PLCγ2-independent stimulation. Carriers and non-carriers had similar serological responses to SARS-CoV-2 vaccination. Conclusion: Compared to non-carriers, immune profiles from carriers more closely resembled those from younger individuals, suggesting that p.P522R associates with resilience against immunological aging.