Through work in his laboratory, immunology researcher Henrique Borges da Silva, Ph.D., aims to understand how extracellular nucleotides regulate the immune system. Nucleotides are produced by and influence numerous intracellular pathways. In diverse circumstances, however, nucleotides are released into the extracellular environment and are sensed by specific receptors called purinergic receptors. Immune cells are not devoid of this process; many purinergic receptors are expressed by the immune system.
The main focus of the research in Dr. Borges da Silva's laboratory is determining how one of these nucleotides, extracellular ATP (eATP), affects transcriptional, metabolic and functional mechanisms of CD8-positive T cells in response to viral infections and cancer. This stems from fundamental discoveries made by Dr. Borges da Silva that showed a crucial role for the eATP purinergic receptor P2RX7 in the establishment of CD8-positive T cell memory. Dr. Borges da Silva aims to expand these findings by using a wide range of current and new experimental tools.
- Understanding how P2RX7 controls long-lived memory CD8-positive T cells. P2RX7 is crucial for the establishment of long-lived memory CD8-positive T cells in the circulation (central memory cells) and in barrier tissues (resident memory cells). The mechanisms through which these populations are influenced by the expression of this molecule still isn't completely understood. Preliminary data suggest a role for both promotion of mitochondrial function and induction of the transforming growth factor beta signaling pathway. Dr. Borges da Silva's lab is investigating how these pathways are influenced by upregulation of P2RX7 during distinct phases of the immune response to viral infection.
- Identifying the relevant eATP sources for CD8-positive T cell immune responses in vivo. ATP can be released either passively via inflamed or dying cells or actively through membrane channels or vesicles. However, assessment of eATP levels in vivo is challenging and often imprecise because of the abundance of membrane-bound and soluble ATPases that shortens the eATP half-life. To circumvent this, Dr. Borges da Silva's lab is establishing tools to allow for qualitative and quantitative analyses of eATP levels sensed by CD8-positive T cells in distinct environments in vivo, adapting fluorescence- and bioluminescence-based ATP probe systems for the study of antigen-specific CD8-positive T cells. These approaches are being tested in conditions where distinct candidate eATP sources are limited or impaired, favoring a better understanding of which in vivo eATP sources are dominantly recognized by CD8-positive T cells during immune responses to viruses or solid tumors.
- Assessing the role of other nucleotide sensors for CD8-positive T cell immune responses. ATP isn't the only nucleotide present in the extracellular microenvironment, and P2RX7 isn't the only nucleotide receptor expressed in CD8-positive T cells. Transcriptional data from Dr. Borges da Silva's work and from other groups show enhanced expression of ATP, ADP, AMP and adenosine receptors. Using high-throughput shRNA screenings and CRISPR-Cas9 knockouts, Dr. Borges da Silva is investigating whether these receptors play a role in CD8-positive T cell immune responses to viruses and solid tumors. This work is expected to provide a more complete overview of how CD8-positive T cells sense the surrounding microenvironment.
Significance to patient care
The generation of fully functional CD8-positive T cells responses (effector and memory) is fundamental for the acquisition of protective immunity to pathogens and to anti-tumor immunity. Despite great advances during the past several decades, many infections lack effective, universal vaccination protocols, such as HIV/AIDS, malaria, influenza and tuberculosis. Likewise, while CD8-positive T cell-based cancer immunotherapy has taken a huge leap during the last few years, many solid tumors lack effective immune-boosting approaches. Lack of understanding about how the surrounding extracellular environment influences CD8-positive T cell function and homeostasis is one of the major knowledge gaps hindering the efficacy of vaccinations and anti-cancer immunotherapy. Dr. Borges da Silva's long-term goal is to detect new candidate extracellular metabolites and CD8-positive T cell receptors that will ultimately be repurposed to establish new therapies and vaccinations and to improve existing ones.
- Recipient, K99/R00 career development grant, National Institutes of Health/National Institute of Allergy and Infectious Diseases (AI139381), 2019-present
- Associate membership, Sigma Xi, 2019
- Honorable mention, Best Ph.D. Thesis, University of Sao Paulo (Brazil), 2015