麻豆传媒

News — Our immune system has an ingenious trick up its sleeve. It remembers past foes, stopping potential sickness in its tracks through a phenomenon known as immunological memory. This is thanks to specialized cells—tissue-resident memory T cells—which reside in vital organs like the small intestine, lungs and other areas. Consider them as frontline guards, stationed exactly where trouble could strike. The endurance of these cells is extraordinary, protecting us from infections we fought decades ago.

Investigations led by University of California San Diego Postdoctoral Scholar Miguel Reina-Campos, Professor Ananda Goldrath and their collaborators at the University of California San Diego and several other institutions have revealed new insights into the metabolism of these specialized immune cells and how they could be enhanced as immune defense weapons against infections and tumors.

“T cells destined for a life-long deployment at barrier tissue sites are professional survivalists,” said Goldrath, a professor in the School of Biological Sciences’ Department of Molecular Biology and senior author of the new paper. “These cells are extremely good at safeguarding tissues across the body, and understanding their unique adaptation strategies teaches us how to design better immune therapeutics.”

The scientific team set out to determine whether these powerful T cells could be tapped for immune system defense and learn more about how such processes unfold. Their findings are published in the journal Nature and include coauthors from the David Geffen School of Medicine at UCLA, UC San Francisco, La Jolla Institute for Immunology, UC San Diego School of Medicine, St. Jude Children’s Research Hospital in Memphis, Tenn. and the University of North Carolina.

“The immune system excels at coping with pathogens and infections, but it struggles against tumors,” said Reina-Campos, the study’s first author. The researchers wondered if these remarkable cells hold the key to unlocking a new era of immune system innovation. This is especially relevant in the battle against stubborn tumors. Picture your immune cells adapting, thriving and evolving within their organ strongholds. The researchers delved deep, investigating the function of thousands of genes fueling these cells’ survival strategy. They ultimately found that T cells in tissue showed a large increase in the complicated production machinery that makes cholesterol molecules. However, a surprising puzzle emerged as the cells appeared primed to make cholesterol, yet a cholesterol-rich diet dampened their effectiveness. It turns out, these clever cells also produce an energy-boosting molecule, coenzyme Q, needed to power the cell’s batteries (mitochondria), as they journey through the intricate process of creating cholesterol.

“What most surprised me is how sensitive and responsive these cells are to the diet,” said Reina-Campos, who noted that cells feature built-in sensor systems that play into their decision-making. “Nature likes cost-effective solutions. If a T cell senses an overabundance of cholesterol, it will shut off the entire internal production line that makes it, the same way you would probably stop grocery shopping and cooking if somebody were to provide free cooked meals daily.” These cells are resourceful and will take what they have available to them, but that is not always in their best interest, he said.

Armed with this new knowledge, the team devised an ingenious way to redirect the cells’ cholesterol-making prowess towards producing more coenzyme Q. Think of it as rerouting a river to nourish different landscapes. Benefitting the research was the existence of a drug that was harnessed to orchestrate this transformative redirection, supercharging the immune cells for a more successful life in tissues. “We are very excited because we found an existing drug that puts this blockade exactly where we need it. When we apply these disruption technologies in the context of tumors, we help T cells maintain fully charged batteries so they can better fight off tumors in mice,” said Reina-Campos.

Another powerful approach to modulating this pathway included statin drugs, which millions use to inhibit the formation of cholesterol and treat cardiovascular disease. The authors found that statins halted the charging of T cell’s batteries; thus, fewer memory cells were found in the tissues. This was because statins block the pathway too far upstream, stopping the production of key molecules for the mitochondria. Although the beneficial cardiovascular effect of statins is undisputable, these results prompt further studies to understand these immunomodulatory effects. On the flip side, statins could offer new insights and tools to dampen unwanted T cell activation in tissues.

The Nature article’s coauthors are: Miguel Reina-Campos, Maximilian Heeg, Kelly Kennewick, Ian Mathews, Giovanni Galletti, Vida Luna, Quynhanh Nguyen, Hongling Huang, J. Justin Milner, Kenneth Hu, Amy Vichaidit, Natalie Santillano, Brigid Boland, John Chang, Mohit Jain, Sonia Sharma, Matthew Krummel, Hongbo Chi, Steven Bensinger and Ananda Goldrath.

Funding for the study was provided by the National Institutes of Health (grants R01 AI067545, P01 AI132122, R01 AI150282, R01 AI072117, R01 CA197363, P01 HL146358 and R01 HL157710); Cancer Research Institute Postdoctoral Fellowship (CRI2943 and CRI4145); a Howard Hughes Medical Institute fellowship (GT14887); National Cancer Institute (grant P30 CA030199 SBP Flow Cytometry Core); National Institutes of Health (grant P30 DK063720 UC San Francisco Parnassus Flow CoLab) and National Institutes of Health SIG (grant S10 OD026929 UC San Diego IGM Core).

Note: Goldrath serves on the scientific advisory boards of ArsenalBio and Foundery Innovations. Chi is a consultant for Kumquat Biosciences. Krummel is a founder and shareholder of PIONYR Immunotherapeutic and Foundery Innovations. Reina-Campos, Galletti and Goldrath have filed a provisional patent application, “Enhancing CAR-T cell performance for cancer immunotherapy,” covering methods related to FDFT1 and PDSS2 manipulation.