Brain Accumulation of Senescence-Like CD8 T Cells During Experimental Cerebral Malaria

Malaria remains a major global public health problem, with high morbidity and mortality rates, particularly due to cerebral malaria (CM), a severe complication caused by protozoan parasites of the Plasmodium genus. CM is associated with an intense inflammatory response and the sequestration of erythrocytes and T cells within the cerebral microvasculature. Although CD8 T cells are implicated in the development of CM, the role of dysfunctional T cells generated through processes of exhaustion and cellular senescence remains poorly understood. T cell senescence is characterized by reduced proliferative capacity, telomere shortening, and expression of molecules such as NKG2D and KLRG1, as well as increased secretion of inflammatory cytokines and cytotoxic mediators. Immunosenescence, previously associated with aging and neurodegenerative diseases, has also been described in parasitic infections, including malaria. Studies in malaria patients suggest peripheral CD4 and CD8 T cells expressing senescence-associated markers, and murine models indicate that the inflammatory environment may induce CD8 T cell senescence in peripheral tissues. In this context, we investigated whether Plasmodium berghei ANKA infection in C57BL/6 mice, an experimental model of cerebral malaria (eCM), was associated with the presence of CD8 T cells displaying senescence-related features in the brain. We evaluated the frequency and phenotype of these cells during infection. We observed a significant increase in the frequency and absolute number of CD8 T cells in the brains of infected animals compared with control mice. Most of these cells expressed KLRG1 and produced IFN-γ and TNF. Although the frequencies of perforin⁺ and granzyme B⁺ CD8 T cells were relatively low, they were approximately twofold higher in the brain than in the spleen. These findings suggest that CD8 T cells with senescence-associated features accumulate in the brain and may contribute to the immunopathology of eCM.