Lucas Stürzbecher ^1,2,3,4 Hendrik Bartolomaeus ^2,3,5,6 Theda Bartolomaeus ^2,3,5,7 Sylvia Bolz ⁸ Andjela Sekulic ¹ Marius Ueffing ^8,9 Simon Clark ^10,8,9 Nadine Reichhart ¹ Sergio Crespo-Garcia ¹¹ Nicola Wilck ^12,2,3,5 Olaf Strauss ^1*

• ¹ Department of Ophthalmology, Charité University Medicine Berlin, Berlin, Germany
• ² Experimental and Clinical Research Center, Charite University Medicine Berlin, Berlin, Baden-Wurttemberg, Germany
• ³ Max Delbrück Center for Molecular Medicine, Helmholtz Association of German Research Centers (HZ), Berlin, Baden-Wurttemberg, Germany
• ⁴ Eye Center, Medical Center, University of Freiburg, Freiburg, Germany
• ⁵ German Center for Cardiovascular Research (DZHK), Berlin, Berlin, Germany
• ⁶ Institute of Experimental Biomedicine, University Hospital of Würzburg, Würzburg, Bavaria, Germany
• ⁷ Charité University Medicine Berlin, Berlin, Baden-Wurttemberg, Germany
• ⁸ Ophthalmological Research Institute, University of Tübingen, Tübingen, Baden-Württemberg, Germany
• ⁹ Department für Augenheilkunde, Universitätsklinikum Tübingen, Tübingen, Baden-Württemberg, Germany
• ¹⁰ Lydia Becker Institute of Immunology and Inflammation, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, England, United Kingdom
• ¹¹ École d'optométrie, Université de Montréal, Montreal, Quebec, Canada
• ¹² Department of Nephrology and Medical Intensive Care, Charité University Medicine Berlin, Berlin, Brandenburg, Germany

Introduction: Age-related macular degeneration (AMD) is a leading cause of blindness with limited treatment options. Dysfunction of the retinal pigment epithelium (RPE) is a unifying salient feature of the pathology and a primary end-point damage leading to complications such as geographic atrophy (GA), which represents the most common end-stage of AMD.Methods: Human and murine ocular tissues were used for histological examinations. Furthermore, flow cytometry and gene expression analysis were used on ocular and splenic tissues of Cx3cr1 GFP/GFP and C57BL/6J mice at 8 and 12 months of age to characterize the dynamics of local and systemic T cell populations.Results: We show the presence of memory T cells such as CD45RO + cells in the choroid and retina of patients with AMD with a peak of abundance in early stages of AMD. As further evidence for the contribution of the adaptive immune system to GA we identified an increased frequency of CD44 + CD69 + KLRG1 + T cells and para-inflammation of the retina in a mouse model that mimics features of GA. Importantly, the activation of T cells found at early AMD-like stages prior to degeneration possessed long-lasting cytotoxic properties and adopted typical features of senescent immune cells.T cells were intimately associated with the RPE, suggesting transmigration and participating in local micro-inflammation. Discussion: Our data support that activation and accumulation of memory T cells can be considered as a hallmark of early AMD, and that adaptive immunosenescence likely to contribute to the chronic inflammation associated with RPE damage and the progression to large lesions as seen in GA.