gms | German Medical Science

Background: Age-related decline in immune cell functions (immunosenescence), such as a decrease in T-cell function, may contribute to the development of rheumatoid arthritis (RA). In aged people, senescent T cells produce low amounts of pro-inflammatory cytokines and tend to proliferate on low level leading to low-grade inflammation. However, cellular metabolism modulates effector functions such as cytokine production and proliferation in T cells by providing energy and building blocks. Naïve and memory CD4⁺ T cells are relatively metabolic quiescent immune cells. Currently, metabolic phenotype of naïve and memory CD4⁺ T cells and how metabolism affects functions of naïve and memory CD4⁺ T cells in aged people are not well understood. Therefore, we analyzed the differences in metabolic phenotype of peripheral naïve and memory CD4⁺ T cells of young and aged healthy donors.

Methods: Naïve and memory CD4⁺ T cells were isolated from PBMCs of 5 ‘young’ donors (23-32 years, 26.6±3.4 years) and 4 ‘aged’ donors (54-67 years, 62.3±5.7 years) using MACS^TM technology. Purity and vitality of isolated cell fractions were assessed by flow cytometry. Ex vivo naïve and memory CD4⁺ T cells were analyzed by Seahorse^TM Technology to determine oxygen consumption rate andproton efflux rate (PER) using Mito Stress Test and Glycolytic Rate Assay, respectively.

Results: Memory CD4+ T cells demonstrated a higher (i) maximal respiration rate, (ii) spare respiratoy capacity, (iii) ratio of maximal respiration/basal respiration, (iv) proton leak, (v) basal glycolytic rate, (vi) basal PER and (vii) post 2-DG acidification rate than naïve CD4+ T cells. Moreover, naïve CD4+ T cells from 'aged' donors displayed a higher proton leak than naïve CD4+ T cells from 'young' donors.

Conclusion: Here we demonstrate higher mitochondrial and glycolytic capacity of human ex vivo memory CD4+ T cells as compared to naïve T-helper cells which can be interpreted by mitochondrial biogenesis and higher glycolytic rate supporting the idea of being prepared for rapid recall reaction. Our preliminary data on the impact of aging already demonstrate a higher proton leak in mitochondria of aged donors especially in naïve T cells which can be assumed to result in a lack of energy upon activation which may lead to a decrease in T-cell function. Thus, an increase in proton leakage in T cells may contribute to the development of RA during aging.