The role of DDX41 on the differentiation and function of regulatory T lymphocytes

• Grant number: 20/04170-1
• Support Opportunities: Scholarships in Brazil - Doctorate
• Start date: September 01, 2020
• End date: February 28, 2025
• Field of knowledge: Biological Sciences - Pharmacology
• Principal Investigator: José Carlos Farias Alves Filho
• Grantee: Gabriel Azevedo Públio
• Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Associated research grant: 13/08216-2 - CRID - Center for Research in Inflammatory Diseases, AP.CEPID
• Associated scholarship(s): 23/05358-2 - The role of STING signaling pathway on the differentiation of regulatory T cells induced by herpes simplex virus-1 (HSV-1) infection, BE.EP.DR

Abstract

Regulatory T lymphocytes (Tregs) are cells that perform immunosuppressive functions important for the maintenance of immune homeostasis and for modulating the inflammatory response. In this sense, the search for understanding the mechanisms that participate in the process of activation, differentiation, and stability of Tregs can provide new therapeutic approaches. The immune system has pattern recognition receptors (PRRs) that act as intracellular sensors capable of recognizing proteins and nucleic acids associated with tissue damage or infections. This process is widely studied on innate immune cells, however, these sensors can present different activities when activated in adaptive immune cells, such as T lymphocytes. An example of this is the activation of STING (STimulator of Interferons Genes). This is an intracellular free cyclic dinucleotide receptor that has been extensively studied in innate immunity. Cyclic dinucleotides are molecules that were initially identified in bacteria and viruses. Data from our research group demonstrated that activation of lymphocytes with cyclic dinucleotides induces greater expression of the transcription factor Foxp3 when cultivated under differentiation conditions for Tregs. DEAD-box helicase 41 (DDX41) is an RNA helicase member of the DEAD box helicase family that acts as a cytosolic DNA sensor, aiding STING activation. However, some research groups have observed that DDX41 does not appear to participate in the anti-viral response process against DNA viruses. In addition to its role in innate immunity, somatic and germline mutations in DDX41 are associated with myelodysplastic syndromes and/or leukemias. Furthermore, a direct interaction between FoxP3 and DDX41 proteins has been reported. Based on this, the present work aims to understand the role of the DDX41 protein in the function and differentiation of regulatory T cells. (AU)

Scientific publications

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

ALVES DAMASCENO, LUIS EDUARDO; MARTELOSSI CEBINELLI, GUILHERME CESAR; FERNANDES, MARIANE FONT; NASCIMENTO, DANIELE CARVALHO; PUBLIO, GABRIEL AZEVEDO; RAMIREZ VINOLO, MARCO AURELIO; OLIVEIRA, SERGIO COSTA; SPARWASSER, TIM; CUNHA, THIAGO MATTAR; CUNHA, FERNANDO QUEIROZ; et al. STING is an intrinsic checkpoint inhibitor that restrains the T(H)17 cell pathogenic program. CELL REPORTS, v. 39, n. 8, p. 15-pg., 2022-05-24. (19/15070-0, 20/04170-1, 18/17542-4, 13/08216-2)