Chronic SIV-Induced neuroinflammation disrupts [CCR7.sup.+] [CD4.sup.+] T cell immunosurveillance in the rhesus macaque brain

[CD4.sup.+] T cells survey and maintain immune homeostasis in the brain, yet their differentiation states and functional capabilities remain unclear. Our approach, combining single-cell transcriptomic analysis, ATAC-Seq, spatial transcriptomics, and flow cytometry, revealed a distinct subset of [CCR...

Full description

Saved in:
Bibliographic Details
Published in:The Journal of clinical investigation 2024-05, Vol.134 (9)
Main Authors: Elizaldi, Sonny R, Hawes, Chase E, Verma, Anil, Lakshmanappa, Yashavanth Shaan, Dinasarapu, Ashok R, Schlegel, Brent T, Rajasundaram, Dhivyaa, Li, Jie, Durbin-Johnson, Blythe P, Ma, Zhong-Min, Pal, Pabitra B, Beckman, Danielle, Ott, Sean, Raeman, Reben, Lifson, Jeffrey, Morrison, John H, Iyer, Smita S
Format: Article
Language:English
Subjects:
Analysis
B cells
Causes of
CD4 lymphocytes
Central nervous system diseases
Chemokine receptors
Chromatin
Development and progression
Health aspects
Interleukins
Physiological aspects
Simian immunodeficiency virus
Surveys
T cells
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:[CD4.sup.+] T cells survey and maintain immune homeostasis in the brain, yet their differentiation states and functional capabilities remain unclear. Our approach, combining single-cell transcriptomic analysis, ATAC-Seq, spatial transcriptomics, and flow cytometry, revealed a distinct subset of [CCR7.sup.+] [CD4.sup.+] T cells resembling lymph node central memory ([T.sub.CM]) cells. We observed chromatin accessibility at the CCR7, CD28, and BCL-6 loci, defining molecular features of [T.sub.CM]. Brain [CCR7.sup.+] [CD4.sup.+] T cells exhibited recall proliferation and interleukin- 2 production ex vivo, showcasing their functional competence. We identified the skull bone marrow as a local niche for these cells alongside CNS border tissues. Sequestering [T.sub.CM] cells in lymph nodes using FTY720 led to reduced [CCR7.sup.+] [CD4.sup.+] T cell frequencies in the cerebrospinal fluid, accompanied by increased monocyte levels and soluble markers indicating immune activation. In macaques chronically infected with SIVCL757 and experiencing viral rebound due to cessation of antiretroviral therapy, a decrease in brain [CCR7.sup.+] [CD4.sup.+] T cells was observed, along with increased microglial activation and initiation of neurodegenerative pathways. Our findings highlight a role for [CCR7.sup.+] [CD4.sup.+] T cells in CNS immune surveillance, and their decline during chronic SIV highlights their responsiveness to neuroinflammation.
ISSN:0021-9738
DOI:10.1172/JCI175332