Elmzzahi, T. | Search bioRxiv

bioRxiv2025

Molecular determinants of brain-resident CD8+ T cell formation and function

Tissue-resident memory T (Trm) cells are strategically located to provide frontline protection upon antigen re-encounter while possessing tissue-specific transcriptional programs. Whether brain Trm cells similarly adapt to their tissue environment, and to what extent their molecular signature is altered in neuropathology, remains unclear. Here we profile brain Trm cells under homeostasis and in the contexts of aging, beta-amyloidosis, and systemic viral infection. From these studies, a tissue-specific CD8+ T cell landscape emerged, defined by the expression of the transcription factor TCF-1 and the inhibitory receptor PD-1. TCF-1 was critical for the formation and phenotypic maturation of brain CD8+ Trm cells, while PD-1 signaling was necessary for robust effector function and antigen-specific recall response. In addition, the cytokine transforming growth factor (TGF)-{beta} was required for the differentiation of brain CD8+ Trm cells and restricted their transition into effector-like cells upon antigenic rechallenge. These findings highlight common as well as tissue-specific features of brain CD8+ Trm cells and provide insights into the molecular mechanisms governing their formation and function.

immunology↗

bioRxiv2024

Disease-associated microglia and activation of CD8+ T cells precede neuronal cell loss in a model of hereditary spastic paraplegia

In central nervous system (CNS) diseases characterized by late-onset neurodegeneration, the interplay between innate and adaptive immune responses remains poorly understood. This knowledge gap is amplified by the prolonged nature of these diseases, complicating the delineation of brain-resident and infiltrating cells. Here, we conducted a comprehensive profiling of innate and adaptive immune cells across various CNS regions in a murine model of spastic paraplegia 15 (SPG15), a complicated form of hereditary spastic paraplegia (HSP). Using fate-mapping of bone marrow-derived cells via genetic labeling, we identified microgliosis and microglial MHC-II upregulation accompanied by infiltration and local expansion of T cells in the CNS of Spg15-/- mice. Single-cell analysis revealed an increase of disease-associated microglia (DAM) and clonal expansion of effector CD8+ T cells across CNS regions occurring prior to neuronal loss. Analysis of potential cell-cell communication pathways suggested bidirectional interactions between DAM and effector CD8+ T cells potentially contributing to disease progression in Spg15-/- mice. In summary, we identified a shift in microglial phenotypes associated with recruitment and clonal expansion of T cells as a new characteristic of Spg15-driven neuropathology. Targeting activated microglia, CD8+ T cells and their communication represent promising avenues to prevent the loss of neuronal function in HSP.

immunology↗