Telomerase Mediates Lymphocyte Proliferation but Not the Atherosclerosis-Suppressive Potential of Regulatory T-Cells

• DOI: 10.1161/atvbaha.117.309940
• Publication Date: 2018-03-29T09:05:13Z
• Authors: Gavin David Richa...; Andrew Sage; Karim Bennaceur; Nayef Al Zhrany; Jose Coelho-Lima; Emily Dookun; Lilia Draganova; Gabriele Saretzki; David T. Breault; Ziad Mallat; Ioakim Spyridopoulos
• Keywords: CD4-Positive T-Lymphocytes; Male; lymphocytes; 570; Mice, Knockout, ApoE; 610; models, animal; Lymphocyte Activation; telomerase; T-Lymphocytes, Regulatory; models; 03 medical and health sciences; Animals; oxidative stress; animal; Telomerase; Cells, Cultured; Cell Proliferation; Mice, Knockout; 0303 health sciences; Basic Sciences; Telomere Homeostasis; Atherosclerosis; Adoptive Transfer; DNA-Binding Proteins; Disease Models, Animal; Oxidative Stress; Female; atherosclerosis; Signal Transduction

Objective— Atherosclerosis is an age-related disease characterized by systemic oxidative stress and low-grade inflammation. The role of telomerase and telomere length in atherogenesis remains contentious. Short telomeres of peripheral leukocytes are predictive for coronary artery disease. Conversely, attenuated telomerase has been demonstrated to be protective for atherosclerosis. Hence, a potential causative role of telomerase in atherogenesis is critically debated.

Approach and Results—

In this study, we used multiple mouse models to investigate the regulation of telomerase under oxidative stress as well as its impact on atherogenesis in vitro and in vivo. Using primary lymphocytes and myeloid cell cultures, we demonstrate that cultivation under hyperoxic conditions induced oxidative stress resulting in chronic activation of CD4 + cells and significantly reduced CD4 + T-cell proliferation. The latter was telomerase dependent because oxidative stress had no effect on the proliferation of primary lymphocytes isolated from telomerase knockout mice. In contrast, myeloid cell proliferation was unaffected by oxidative stress nor reliant on telomerase. Telomerase reverse transcriptase deficiency had no effect on regulatory T-cell (T reg ) numbers in vivo or suppressive function ex vivo. Adoptive transfer of telomerase reverse transcriptase – /– T regs into Rag2 –/– ApoE –/– (recombination activating gene 2/apolipoprotein E) double knockout mice demonstrated that telomerase function was not required for the ability of T regs to protect against atherosclerosis. However, telomere length was critical for T reg function.

Conclusions—

Telomerase contributes to lymphocyte proliferation but plays no major role in T reg function, provided that telomere length is not critically short. We suggest that oxidative stress may contribute to atherosclerosis via suppression of telomerase and acceleration of telomere attrition in T regs .