Role and regulation of methylarginine effector TDRD3 in T cell immunity

T cell activation is a crucial step in initiating adaptive immune responses against pathogens such as viruses and bacteria. This process requires precise transcriptional regulation to ensure a rapid and robust immune response while preventing aberrant activation that could lead to autoimmunity or excessive inflammation. However, the mechanisms by which T cells achieve this balance to maintain immune homeostasis remain unclear. In recent years, protein arginine methylation has emerged as a key regulatory mechanism in T cell biology, modulating activation, differentiation, and cytokine production. Although targeting protein arginine methyltransferases (PRMTs) has shown promise in regulating immune responses, their therapeutic potential is limited by systemic adverse effects due to the essential roles of these enzymes in many fundamental cellular processes. We propose that targeting specific downstream effectors of arginine methylation may offer a more precise therapeutic strategy while minimizing adverse effects on normal tissues. To achieve this, we focus on Tudor domain-containing protein 3 (TDRD3), the primary methylarginine reader and effector that plays a key role in arginine methylation-mediated cellular processes, including transcription regulation. Our preliminary data reveal that, although TDRD3 is not required for normal development, knockout of TDRD3 in CD4+ T cells confers resistance to experimental autoimmune encephalomyelitis by impairing T cell activation, proliferation, and survival. Mechanistically, TDRD3 functions as a transcriptional coactivator for genes critical to T cell activation, including interleukin-2 (IL-2), the master regulator of T cell-mediated immune responses. Additionally, we discovered that T cell activation is associated with a robust increase in R-loops—three- stranded DNA structures composed of a DNA/RNA hybrid and a single-stranded DNA—particularly at the IL-2 gene promoter. We also identified a novel TDRD3-interacting protein complex that may be responsible for R- loop regulation during T cell activation. The goal of this project is to define how TDRD3-regulated R-loop dynamics influence T cell-mediated immune responses. Specifically, we will: 1) elucidate the molecular mechanisms by which TDRD3 acts as a coactivator for transcription activation, focusing on IL-2 as a major target; 2) investigate the role of TDRD3 and its interacting protein complex in R-loop regulation during T cell activation; and 3) evaluate the therapeutic potential of targeting TDRD3-mediated transcription regulation to modulate T cell immune responses in autoimmune and infectious disease models. Results from these experiments will uncover fundamental mechanisms of transcription regulation in T cells. The key pathways revealed in this study could serve as novel targets for treating immunological disorders. Project Number: 1R01AI195711-01 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of Allergy and Infectious Diseases (NIAID) | Principal Investigator: Yanzhong Yang (+1 co-PI) | Institution: BECKMAN RESEARCH INSTITUTE/CITY OF HOPE, DUARTE, CA | Award Amount: $794,183 | Activity Code: R01 | Study Section: Molecular and Structural Immunology Study Section[MSI] View on NIH RePORTER: https://reporter.nih.gov/project-details/1R01AI19571101