T Cell Dysfunction in Neurodegenerative Conditions

Chronic inflammation and dysfunction of immune cells is a characteristic of neurodegenerative conditions. Attention is usually given to the innate immune cells of the central nervous system in this context, but it is also the case that the adaptive immune system outside the brain tends towards dysfunction in older individuals suffering from age-related disease. Researchers here review what is known of T cell exhaustion, senescence, and other issues in older individuals. It is hoped that clearing these problematic cells from the immune population, such as via the use of senolytic drugs to destroy senescent cells, will have reduce the risk and slow the progression of neurodegenerative conditions.

CD8+ T lymphocytes are adaptive immune cells that, upon antigen recognition, undergo a complex differentiation process. In acute inflammatory responses, when antigen is effectively cleared, short-lived effector T cells undergo controlled apoptosis, while long-lived effector T lymphocytes differentiate into memory T cells, thus efficiently resolving the inflammatory reaction. However, during chronic inflammatory conditions, this natural resolution is impaired, and CD8+ T lymphocytes become exhausted or senescent, retaining a neurotoxic potential and contributing to several neurodegenerative diseases.

CD8+ T cells, reacting against self and non-self antigens are clonally expanded in all brain disorders discussed in this review, including Alzheimer's disease, Parkinson's disease, and multiple sclerosis. It is worth noting that although these disorders may have distinct causes, occurrence rates, and clinical presentations, they share common immunopathological characteristics. These include the circulating origin of central nervous system-invading CD8+ T lymphocytes, the clonal expansion of CD8+ T cells, and phenotypical traits that resemble senescence.

In the light of growing evidence suggesting that senescent and exhausted CD8+ T cells contribute to aging and various brain disorders, a promising therapeutic approach for these conditions may be represented by targeting deleterious functions of CD8+ T cells. Indeed, targeting senescent and exhausted CD8+ T cells may create a personalized neuroimmunotherapy, with the ultimate goal to rejuvenate T cells through tailored diagnostic and therapeutic protocols. Strategies such as epigenetic modulation and using senolytic compounds to induce apoptosis in senescent and exhausted CD8+ T cells may also be explored. Several studies are ongoing to prove the effectiveness of interventions targeting tissue-damaging senescent cells, which may slow, prevent, and alleviate disorders in preclinical models. The development of senolytic small molecules that can specifically eliminate senescent cells, may represent a promising strategy for treating multiple CD8+ T cell senescent-mediated disorders and age-related conditions in humans.

Link: https://doi.org/10.3389/fimmu.2023.1233870