Researchers led by Doron Merkler from the University of Geneva have shown how post local infection, a fraction of resting CD8+ tissue resident memory (TRM) cells cross-reacted with antigens of the CNS to become subsequently activated and drive immunopathological responses in the CNS. They reported their findings in the April 13, 2022, online edition of Science Translational Medicine.

CD8+ "killer" T cells in nonlymphoid tissues contribute to localized immune surveillance and confer protection against reinfection. Conversely, aberrantly activated TRM cells may be involved in tissue-damaging proinflammatory responses seen in autoimmune disorders. Indeed, in several neuroinflammatory conditions such as multiple sclerosis (MS), CD8+ T cells have been detected in the cerebrospinal fluid of patients, early after disease onset.

However, the potential implications of these TRM cells in driving neuroinflammation have not been studied in detail.

In the Science Translational Medicine publication, the authors investigated whether resting CD8+ cells that persisted after the clearing of viral infections could initiate immune responses directed against cognate self-antigens in the CNS. Merkler, an associate professor in neuropathology at University of Geneva, and his team established an in vivo murine model of neuroinflammation that allowed for targeted and local reactivation of resting CD8+ TRM that colonized and persisted in the CNS after transient infection with attenuated lymphocytic choriomeningitis virus (LCMV).

The researchers investigated how these resting CD8+ TRM were clonally expanded and reactivated in a time and cell-specific manner upon encountering their cognate neo-self-antigen expressed by glial cells. The reactivated CD8+ cells were capable of differentiating into self-destructive effectors to initiate neuroinflammation, which required help of CD4+ T cells.

The authors next assessed that the reactivated TRM could precipitate immunopathology and disease in an organ-autonomous manner, independently of circulating CD8+ T cells that are formed by destruction of antigenic glial cells. They were able to do so by entering the cell cycle and rapidly acquiring a cytotoxic effector phenotype.

In their paper, the authors wrote that "histological evaluation revealed that TRM reactivation and simultaneous tissue destruction were accompanied by substantial recruitment and activation of other immune cell subsets in the CNS." They observed that the inflamed CNS contained a substantial number of recruited CD4+ T cells and in the absence of CD4+ T-cell help, the activated TRM failed to expand and differentiate into cytotoxic effector cells and lost their tissue-destructive capacity.

The authors assert that their study constitutes a major conceptual advance toward understanding how TRM may be involved in CNS immunopathology and how, under certain circumstances, such cells contribute to aberrant immune processes driving disease progression.

In fact, the findings of this study can explain the observed effectiveness of current treatments in relapsing-remitting early MS that primarily target the circulating immune cell pool. As the disease progresses, TRM increasingly occupy the majority of CD8+ T lymphocytes, which may better escape conventional therapeutic approaches. In early MS disease stages, immunomodulatory treatments that prevent the influx of circulating CD4+ T cells into the CNS will equally interfere with the pathogenic properties of TRM. However, given that such treatments are poorly effective in progressive MS, the authors speculate that tissue destructive CD8+ TRM may become independent from CD4+ T help with time in chronic disease states or that CD4+ TRM may accumulate over time in the CNS.