Functional study of the ectonucleotidase CD39 in CD4+ and CD8+ T lymphocytes during pulmonary infection with influenza virus.

• Grant number: 25/01982-9
• Support Opportunities: Scholarships in Brazil - Master
• Start date: July 01, 2025
• End date: February 28, 2027
• Field of knowledge: Biological Sciences - Immunology - Cellular Immunology
• Principal Investigator: Maria Regina D'Império Lima
• Grantee: Guilherme Henrique Rodrigues Mattos
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

ATP is essential for cellular metabolism, but when released into the extracellular environment during cell activation, stress or death, it can act in cell communication and as a danger signal. At high concentrations, extracellular ATP (eATP) activates the purinergic receptor P2RX7, triggering a calcium influx that intensifies inflammatory responses, leading to excessive immune cell activation and, in extreme cases, cell death. Regulating this process is crucial to prevent tissue damage in severe lung infections, such as tuberculosis and influenza. We recently showed that P2RX7 signaling in CD4+ T cells can aggravate lung infections by promoting the exacerbated migration of effector cells into damaged tissue. The ectonucleotidase CD39, encoded by the Entpd1 gene, plays a key role in regulating purinergic signaling by promoting the dephosphorylation of eATP and generation of ADP and AMP, which are then converted by the enzyme CD73 into adenosine, a mediator with immunoregulatory effects. In this context, the project hypothesizes that CD39's regulatory activity is crucial for the effector function of pathogenic T cells in severe lung infections. Since P2RX7 stimulation contributes to the accumulation of effector T cells in the lung parenchyma, it is expected that the absence of CD39 will intensify this response, resulting in greater tissue damage. However, it is possible that excessive stimulation of P2RX7 leads to cell dysfunction or death. Thus, the project aims to explore the role of CD39 in vascular and parenchymal CD4+ e CD8+ T cells in the infected lung, by evaluating the effects of CD39 inhibition or deficiency, as well as treatment with Apyrase, and analyzing how this modulation influences the localization, differentiation and gene expression of these T cells. This knowledge could contribute to the development of therapies that prevent damage caused by excessive T cell activation in lung infections. (AU)