W150 - Age-associated Increase in Cytotoxic T Lymphocyte-associated Protein 4 (CTLA-4) Expression on Effector T Cells: Potential Implication in Autoimmunity and Immunosenescence

Martin Wasser – Translational Immunology Institute, SingHealth Duke-NUS Academic Medical Centre, Singapore; Katherine Nay Yaung – Translational Immunology Institute, SingHealth Duke-NUS Academic Medical Centre, Singapore; Annie Hui Nee Law – Department of Rheumatology ＆ Immunology, Singapore General Hospital, Singapore; Nicholas Khoo Kim Huat – Translational Immunology Institute, SingHealth Duke-NUS Academic Medical Centre, Singapore; Pavanish Kumar – Translational Immunology Institute, SingHealth Duke-NUS Academic Medical Centre, Singapore; Thaschawee Arkachaisri – KK Women’s and Children’s Hospital, Singapore; Su Li Poh – Translational Immunology Institute, SingHealth Duke-NUS Academic Medical Centre, Singapore; Jingyao Leong – Translational Immunology Institute, SingHealth Duke-NUS Academic Medical Centre, Singapore; Julian Thumboo – Department of Rheumatology ＆ Immunology, Singapore General Hospital, Singapore; Andrea Hsiu Ling Low – Department of Rheumatology ＆ Immunology, Singapore General Hospital, Singapore; Salvatore Albani – Translational Immunology Institute, SingHealth Duke-NUS Academic Medical Centre, Singapore; Joo Guan Yeo – Translational Immunology Institute, SingHealth Duke-NUS Academic Medical Centre, Singapore

Abstract Text: Cytotoxic T lymphocyte-associated protein 4 (CTLA-4) is a crucial immune checkpoint inhibitor expressed on CD4+Foxp3+CD25+ regulatory T cells (Tregs), essential for maintaining immune homeostasis. Interestingly, CTLA-4 is also expressed on CD4+Foxp3-CD25- effector T cells (Teffs). We observed a significant reduction in CTLA-4 expressing Teffs in adult lupus (n=41), compared to age-matched healthy controls, suggesting a putative role of CTLA-4 on Teffs in maintaining immune homeostasis. We, therefore, hypothesise there is a natural age-related increase of CTLA-4 expression in Teffs to counteract the increased exposure to exogenous immune stimuli.

To achieve this, we re-mined the mass cytometry data from PBMCs from 193 healthy individuals (0 to 95 years old) from the Extended Polydimensional Immunome Characterization (EPIC) database.1 Batch effect correction, clustering, and annotation of cell subsets based on marker expression were done. Expectedly, the CTLA-4+ naive Tregs correlated negatively with age (Spearman correlation, r = -0.6497, p< 0.0001) while memory Tregs correlated positively with age (r = 0.6609, p< 0.0001). Interestingly, both naive and memory CTLA-4+Foxp3-CD25- Teffs increased with age (r = 0.3837, p< 0.0001; r = 0.4533, p< 0.0001 respectively). CTLA-4+ Teffs significantly differed between the 0-6 and 6-12 versus 40-60 and 60-95 year-old age groups (Kruskal-Wallis test; Dunn’s multiple comparison tests, p< 0.0001).

Our results suggest that CTLA-4 expression on Teffs may be important for immune homeostasis by increasing the cellular activation threshold to stimuli. Conversely, its increase may contribute to immunosenescence, resulting in increased susceptibility to infection and reduced vaccination responses in the elderly.

1. Yeo JG et al. Nat Biotechnol. 2020 Jun;38(6):679-684.