An inflammatory response in the brain or spinal cord is referred to as neuroinflammation. The synthesis of cytokines, chemokines, reactive oxygen species, and secondary messengers mediates this inflammation. Endothelial cells, peripherally derived immune cells, and resident CNS glia (microglia and astrocytes) all contribute to the production of these mediators. These neuroinflammatory responses have immunological, physiological, biochemical, and psychological effects.
Multiple sclerosis (MS) is an autoimmune neuroinflammatory disease, displaying demyelinating disorder of the central nervous system (CNS). Neurodegeneration (loss of myelin and axons) in MS is caused by an immune response to self-antigens, interrupting signal transmission. Although the cause of MS is unknown, genetic, epigenetic, and environmental factors have been introduced as the possible risk factors of the disease. T cells, a type of lymphocyte, are crucial elements of the adaptive immune system to protect us from pathogens and tumors. However, slef-reative T cells can represent a risk for self-tissues. The MS pathophysiology is mostly believed to be autoimmune demyelination caused by CD4+ T effector cells (Teff, a type of T cells to induce immune reaction or inflammation). However, another type of T cells, called regulatory T (Treg) cells, are able to balance Teff cells to ameliorate over-reaction and reduce inflammation.
Experimental autoimmune encephalomyelitis (EAE) is an animal model for MS that is used in experimental studies. Many aspects of the MS pathophysiology, such as inflammation, immune surveillance, immune-mediated tissue injury, and roles of immune cells, have been revealed by using EAE models. Also, studies have shown that there is a correlation between EAE and MS therapeutic success. However, the majority of these studies—whether they were looking at MS in humans or EAE in mice—have only looked at young people, omitting the age-associated T cell immunological conditions. As a result, little is known about how aged T cells, particularly accumulated and increased CD4+FoxP3+ regulatory T (Treg) cells, affect MS/EAE.
In a new study published in Aging Cell, researcher Dr. Weikan Wang, Rachel Thomas, Jiyoung Oh and led by Professor Dong-Ming Su from University of North Texas proposed that Treg cells can have either a detrimental or beneficial role, which is dependent on their location, either inside the CNS (termed CNS-Treg) or outside the CNS (in the periphery, termed pTreg). Researchers looked at Treg distribution inside and outside the CNS, Treg antigen specificity to myelin oligodendrocyte glycoprotein (MOG) and pan-antigens, and Treg function-associated molecular profiles during EAE in young and old animals to test their hypothesis about how accumulated aged pTreg cells impact late-onset MS using the EAE model in aged mice. Additionally, they showed a modest improvement in the illness in the aged animals and transiently suppressed FoxP3 expression in accumulating pan-pTreg cells.
The research team reported that older EAE mice showed a distinct distribution of pan- and MOG-sp. Treg cells compared to their younger counterparts. They used an aged EAE mouse model to mimeck an older person with MS. Aged animals, in particular, showed low proportions of both pan- and MOG-sp CNS-Treg cells in the inflamed CNS but high proportions of pan-pTreg and low proportions of MOG-specific pTreg cells in their peripheral. They found that, compared to their younger counterparts, aged inflammatory CNS-Treg cells showed greater flexibility, as evidenced by the co-expression of interferon (INF)- and/or interleukine (IL)-17 with FoxP3, which may have an adverse effect on suppressive function and an increase in pathogenesis. Additionally, variations in CNS-Teff clonal growth were noted, which provided insight into the weakened suppressive activity of aged mice’s CNS-infiltrating Treg cells. According to the authors, neither young nor old mice have enlarged CNS-infiltrated Treg clones that make up more than 3%–4% of all CNS-infiltrated Treg clones. There are many unsolved concerns surrounding how CD8+Treg cells contribute to CNS autoimmune inflammation in elderly individuals because investigations of these cells in MS/EAE have been focused on young people or young animals. Therefore, further research into how these cells work in the elderly is necessary.
The study by Professor Dong-Ming Su and his research team offer strong evidence that accumulating and compromised old pTreg cells may not ameliorate the course and severity of late-onset (aged) neuronal autoimmune EAE illness, but may even be harmful. In conclusion, the findings shed the light on how the aged polyclonal CD4+FoxP3+ pTreg cells formed in an inflammatory situation in elderly MS revealed in the animal model EAE do not ameliorate but are harmful to CNS repair processes.
Wang W, Thomas R, Oh J, Su DM. Accumulation of pTreg cells is detrimental in late‐onset (aged) mouse model of multiple sclerosis. Aging Cell. 2022 ;21(6):e13630.