Regulation of regulatory T cell differentiation and function: role of the SLC19a1-STING axis in cellular responses and herpes simplex virus infection

Author(s)

Gabriel Azevedo Públio

• Document type: Doctoral Thesis
• Press: Ribeirão Preto.
• Institution: Universidade de São Paulo (USP). Faculdade de Medicina de Ribeirão Preto (PCARP/BC)
• Defense date: 2025-04-24

Examining board members

José Carlos Farias Alves Filho; Lucas Tabajara Parreiras e Silva; Luis Lamberti Pinto da Silva

• Advisor: José Carlos Farias Alves Filho

Abstract

Immune homeostasis is tightly regulated by regulatory T cells (Tregs), which play a crucial role in controlling inflammatory responses. In this thesis, we investigated the role of the Slc19a1-STING axis in Treg differentiation and function, as well as its influence on the immune response to Herpes simplex virus type 1 (HSV-1) infection. We first demonstrated that Tregs express high levels of the Slc19a1 transporter, enabling the uptake of cyclic dinucleotides (CDNs) and subsequent activation of the STING pathway. STING activation induced the phosphorylation of its signaling components and increased the expression of Ifnb1 and Foxp3, reinforcing Treg stability and immunosuppressive function. Pharmacological inhibition or genetic deletion of Slc19a1 impaired STING activation, reducing Treg differentiation and increasing their plasticity toward inflammatory phenotypes. During HSV-1 infection, we observed that the virus promotes Treg differentiation in a STING-dependent manner. Infection also enhanced the expression of immunosuppressive molecules and stabilized Tregs, preventing their conversion into pro-inflammatory phenotypes. In vivo experiments revealed a significant expansion of Tregs in draining lymph nodes, while transcriptomic analyses indicated STING activation in these cells. Notably, Tregs isolated from infected mice exhibited a transcriptional profile compatible with viral latency, suggesting that these cells may serve as alternative reservoirs for HSV-1. Lastly, metabolic analyses indicated that STING activation impacts Treg energy dependency. Collectively, our findings indicate that the Slc19a1-STING axis is a key regulator of Treg differentiation and function, and that its activation during HSV-1 infection contributes to viral persistence. Targeting this pathway may represent a novel therapeutic strategy for infectious and autoimmune diseases. (AU)

• FAPESP's process: 20/04170-1 - The role of DDX41 on the differentiation and function of regulatory T lymphocytes
• Grantee: Gabriel Azevedo Públio
• Support Opportunities: Scholarships in Brazil - Doctorate