Neuropeptides influence T cell differentiation during viral infections

Vijay K. Kuchroo, PhD, DVM, of the Gene Lay Institute of Immunology and Inflammation at Brigham and Women's Hospital, Massachusetts General Hospital and Harvard Medical School and the Ann Romney Center for Neurologic Diseases at Brigham and Women's Hospital, is the co-corresponding author of an article published in Nature: “Neuropeptide signaling orchestrates T cell differentiation.”

How would you summarize your study for a lay audience?

T helper cells (TH cells) are essential immune cells that help other immune cells function effectively. When activated in response to environmental stimuli, these cells can differentiate into either TH1 cells, which fight against viruses and intracellular pathogens, or TH2 cells, which fight against extracellular pathogens such as bacteria and parasites. However, scientists have not fully understood whether infected tissue itself plays a role in controlling optimal T cell differentiation in response to tissue infection.

Our research has shown that virally infected neurons play an important role by promoting the development of TH1 cells and inhibiting TH2 cells during viral infections. This communication between infected neurons and the immune system occurs through molecules called neuropeptides, which interact with specific receptors on T cells to control their fate. This process is crucial for the body to effectively control viral infections.

What knowledge gap can your study fill?

Our results show that neuroimmune communication plays a crucial role in determining T cell fate and provides a new link between infected tissue (neurons) and the differentiation of T cell subsets.

What methods or approaches did you use?

Our team investigated the regulatory mechanisms that control the optimal differentiation of T cells into certain lineages while inhibiting others. To this end, we used a technique called single-cell RNA sequencing (scRNA-seq) to study how genes are expressed over time, studying two types of immune cells (TH1-TH2) in a cell culture system. We also used CRISPR screening to find out which regulators help control T cell development in Th1 and Th2 cells.

By combining various gene and cell biology techniques, we were able to show using preclinical models that the neuropeptide receptor RAMP3 plays a key role in the development of T cells.

What did you find?

We have shown that neuroimmune circuits influenced by neuropeptides and their receptors play a critical role in determining T cell fate. We also examined how neuropeptides ensure optimal T cell differentiation and elicit robust antiviral responses.

What are the effects?

Our study suggests that changes to neuroimmune circuits may help balance different types of T cells and lead to better immune responses. For example, previous research has shown that an imbalance in TH2 differentiation versus TH1 correlates with increased mortality in patients with COVID-19. Targeting the neuroimmune signaling pathways that regulate T cell fate decisions could provide new therapeutic options for patients with severe COVID-19 infections, cancer and other autoimmune diseases.