#ACTRIMS2021 – Research Examines T-cells’ Anti-inflammatory Potential
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Regulatory immune cells expressing the melanoma cell adhesion molecule (MCAM) dampen inflammation at sites of nerve damage in multiple sclerosis (MS), making them a potential therapeutic candidate.
T-cells play a central role in the body’s immune response, recognizing and destroying foreign molecules and diseased cells. This process goes awry in MS when “autoreactive” T-cells wrongly recognize the body’s own myelin — a nerve-insulating molecule — as foreign and attack it, triggering an inflammatory response.
Regulatory T-cells (Tregs) guard against such autoimmune reactions by suppressing the proliferation of immune pro-inflammatory cells.
Both autoreactive T-cells and Tregs must cross the blood-brain barrier (BBB) in order to act on neurons in the brain. They accomplish this by employing a class of proteins called cell adhesion molecules (CAMs).
If Tregs’ anti-autoimmune abilities are ever to be harnessed therapeutically, scientists need to know which CAM these cells use to access the central nervous system (CNS, the brain and spinal cord).
Researchers from the University of Montreal, in Canada, discovered that MCAM plays an essential role in this process.
Jennifer Sebali, the study’s lead author, presented her team’s findings in a talk titled “Role of MCAM+ Regulatory T Cells in Multiple Sclerosis,” at the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) Forum 2021, held virtually Feb. 25–27.
The investigators isolated Tregs from the blood and cerebrospinal fluid (CSF) of people with MS and of healthy controls. They found that patients with various MS subtypes all had similar Treg blood levels.
“We first conclude that Treg levels are maintained in different phases of MS,” Sebali said.
When looking at MCAM positive (MCAM+) Treg cells, the team found that MS patients and controls largely differed, with untreated relapsing-remitting MS (RRMS) patients showing significantly higher levels of MCAM+ Tregs. This suggested “that these Tregs might be getting ready to migrate by [activating] MCAM,” Sebali said.
Tregs were present in higher levels in the CSF of RRMS patients than in their blood, and these cells expressed cell migration-related molecules and strong MCAM activity. Together, these results suggested that MCAM+ Tregs in the CSF of MS patients were both activated and functional, and further implicated MCAM in Treg migration.
These MCAM+ Tregs also produced more anti-inflammatory molecules — namely interleukin-10 and granzyme B — compared with Tregs not expressing MCAM, indicating that these MCAM+ Tregs maintained their anti-inflammatory abilities inside the CNS.
“MCAM+ Tregs seem to have a more functional and anti-inflammatory [profile] than their MCAM negative counterparts [Tregs not expressing MCAM],” Sebali said.
To verify that MCAM+ Tregs do, in fact, migrate from the blood to the CNS, Sebali and her team compared the concentration of these cells around spinal cord lesions at different disease course time points in experimental autoimmune encephalomyelitis (EAE) mice, an established animal model of MS.
MCAM+ Tregs in these mice increased during periods of remission, reinforcing their involvement during this phase of MS.
Based on the results, the investigators suggested that MCAM might be essential to bringing Tregs into the CNS, where they potentially may reduce myelin-damaging inflammation.
“Altogether,” Sebali concluded, “MCAM might be a very important adhesion molecule for Tregs migration into the brain,” suggesting MCAM+ Tregs could be envisioned as a potential therapeutic treatment for MS.