Dissection of the Human T-Cell Receptor γ Gene Repertoire in the Brain and Peripheral Blood Identifies Age- and Alzheimer's Disease-Associated Clonotype Profiles.

Maria Aliseychik,Fedor Gusev,Evgeny Rogaev,Arya Biragyn,Tatiana Andreeva,Anastasia Grigorenko,Anton Patrikeev

doi:10.3389/fimmu.2020.00012

Abstract

The immune system contributes to neurodegenerative pathologies. However, the roles of γδ T cells in Alzheimer's disease (AD) are poorly understood. Here, we evaluated somatic variability of T-cell receptor γ genes (TRGs) in patients with AD. We performed deep sequencing of the CDR3 region of TRGs in patients with AD and control patients without dementia. TRG clones were clearly detectable in peripheral blood (PB) and non-neuronal cell populations in human brains. TRG repertoire diversity was reduced during aging. Compared with the PB, the brain showed reduced TRGV9 clonotypes but was enriched in TRGV2/4/8 clonotypes. AD-associated TRG profiles were found in both the PB and brain. Moreover, some groups of clonotypes were more specific for the brain or blood in patients with AD compared to those in controls. Our pilot deep analysis of T-cell receptor diversities in AD revealed putative brain and AD-associated immunogenic markers.

Highlights

Low levels of chronic inflammation in aging, often termed “inflammaging,” are associated with immune dysregulation and represent a risk factor for decreased brain function and a hallmark of Alzheimer’s disease (AD)
Because cell sorting cannot be applied to frozen peripheral blood (PB) and brain samples, we designed an approach based on a modified BIOMED2 consortium multiplex polymerase chain reaction (PCR) system followed by library preparation and deep sequencing to characterize the T-cell receptor γ genes (TRGs) repertoires
To the best of our knowledge, in this study we present for the first time results of T-cell receptors (TCRs) repertoire profiling in patients with AD

Summary

Introduction

Low levels of chronic inflammation in aging, often termed “inflammaging,” are associated with immune dysregulation and represent a risk factor for decreased brain function and a hallmark of Alzheimer’s disease (AD). Neuroinflammation occurs through activation of brain innate immune cells, such as microglia and macrophages, and further exacerbates the pathogenesis of AD [1]. T cells can be induced by peripheral or brain antigen-presenting cells, such as microglia and macrophages, which take up and present antigens associated with AD. Animal modeling experiments have suggested that disease outcomes may depend on the type of brain-infiltrating T cells present in patients. In a rat model β-synuclein-specific T cells were found to invade gray

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