Caption: Scientific image representing microglia cells. Image courtesy of Giovanne B. Diniz, John H. Morrison and Smita S. Iyer.
By Phoebe Ingraham Renda
The immune system is best known for its role as the body’s security system against pathogens, but its responsibilities don’t stop there. It also monitors and regulates day-to-day cellular wear and tear, called immunosurveillance. However, when it comes to the brain, the way immune cells travel through the body to conduct this surveillance is a black box.
Research led by School of Medicine faculty at the University of Pittsburgh, published in The Journal of Clinical Investigation, shows that knowing the details of that black box is critical to developing therapies for neuroinflammation caused by infectious diseases.
Smita Iyer, associate professor of pathology (Division of Experimental Pathology) and of medicine (Division of Infectious Diseases) and co-corresponding author on the study with Reben Raeman, associate professor of pharmacology and chemical biology, focuses her research on understanding how T cells operate. T cells, she says, are constantly patrolling your tissues to check and see, “hey, is everything OK?”
But as these T cells do their rounds, viruses can co-opt their immunosurveillance role by hitching a ride and using them as a taxi service to invade organs. Human immunodeficiency virus (HIV), for example, hijacks CD4 T cells to set up shop in the brain, where it can trigger inflammation in the central nervous system. That neuroinflammation often happens in the brain parenchyma, says Iyer—the functional tissue that is responsible for cognition, sensation and movement.
Beyond HIV, neuroinflammation is relevant to multiple neurodegenerative diseases, including Alzheimer's and Parkinson's, but also aging-associated dementia, says Iyer. She also notes a growing clinical recognition that neuroinflammation is involved in metabolic diseases, such as type 2 diabetes and metabolic dysfunction-associated steatotic liver disease: “This is extremely important because neuroinflammation is only going to grow as a health concern with aging and the increased prevalence of metabolic disease.”
The knowledge that T cells could enter the brain is also a relatively recent scientific finding, she says, and is one of the key reasons T cells have been overlooked in previous research studies. “They are a small population of cells in the brain for sure, but they can have huge impacts as our study has shown,” says Iyer.
In their study to mitigate HIV-induced neuroinflammation, Iyer and colleagues assessed whether an existing U.S. Food and Drug Administration-approved multiple sclerosis biologic, called natalizumab, could be repurposed to keep viral-hijacked T cells out of the brain.
In the context of multiple sclerosis, which is a neurodegenerative autoimmune disease, natalizumab works by blocking a molecule called α4 integrin on the surface of T cells, which impairs their ability to enter the central nervous system. To their surprise, in the context of infectious disease, viral loads in the brain were higher following natalizumab use in animal models. With the help of Raeman’s team at the Organ Pathobiology and Therapeutics Institute who developed a system to study mechanisms of α4 integrin trafficking for metabolic diseases of the liver, Iyer identified that α4 integrin was not essential for CD4 T cells to enter the brain but was important for CD8 T cells, which kill infected cells. In effect, their results showed that taking natalizumab in the context of infectious disease was proinflammatory, because it inhibits CD8 T cell function, allowing hijacked CD4 T cells to enter the brain unchecked.
The result reminds researchers that drugs approved for autoimmune disease do not automatically translate to infectious disease therapies and repurposing drugs should be approached with caution.
These findings, she adds, underscore why a deep, mechanistic understanding of immune cells and their roles in neuroinflammation are needed to design stronger, more effective therapeutics not only for HIV but across the spectrum of infectious diseases. Iyer also notes that this initial study did not examine the interactions between T cells and microglia, which she describes as the resident security system of your brain.
“Rather than siloing both of these cells, we need to study them together and understand what is going on with their interaction and how it is affecting the brain.”
Building on their findings, Iyer and her team will focus on studying those interactions to better define the roles of T cells in neuroinflammation across pathological contexts.