Molecular determinants of brain-resident CD8+ T cells in health and disease

Abstract

T cells populate the brain at steady state, where they contribute to its physiology and protect the host against re-infection. Tissue-resident memory T (Trm) cells residing in various non-lymphoid tissues are known to adopt tissue-specific transcriptional programs shaped by the tissue microenvironment. Whether brain-resident CD8+ T cells similarly acquire a tissue-specific transcriptional landscape, and to what extent this molecular signature is altered in neuropathology, remain to be determined. In addition, the signaling pathways and transcription factors that govern the formation, maintenance, and function of brain CD8+ Trm cells are largely unknown. In this study, I unravel the heterogeneity of brain-resident CD8+ T cells in mice using single-cell RNA-sequencing and high-parameter flow cytometry. Specifically, I profile brain CD8+ Trm cells in naïve young adult mice, and in the contexts of cerebral amyloidosis, systemic acute and chronic viral infection, and aging. From these studies, a framework of a predominantly tissue-specific CD8+ T cell landscape has emerged, largely defined by the expression of the inhibitory receptor PD-1, the surface molecule Ly6C, and the transcription factor TCF-1. Conversely, CD8+ T cells adopted context-specific phenotypic and functional properties in chronic viral infection. Interrogating the molecular determinants of brain CD8+ T cell differentiation and maintenance, I found that TCF-1 promotes the differentiation of brain CD8+ T cells yet negatively regulates the population size upon antigen-specific rechallenge. In addition, PD-1 signaling was important for the differentiation of optimal CD8+ T cell memory in the brain, and was necessary for robust secondary expansion and effector function upon antigen re-encounter. Finally, the cytokine transforming growth factor (TGF)-β was required for the formation of brain-resident CD8+ T cells and for constraining their transition into effector-like cells upon antigenic rechallenge. Taken together, these findings highlight common, tissue-specific as well as context-specific features of brain CD8+ Trm cells, and provide insights into the molecular mechanisms orchestrating their formation and function.