Chronic SIV-Induced neuroinflammation disrupts CCR7+ CD4+ T cell immunosurveillance in the rhesus macaque brain
Sonny R. Elizaldi, Chase E. Hawes, Anil Verma, Yashavanth Shaan Lakshmanappa, Ashok R. Dinasarapu, Brent T. Schlegel, Dhivyaa Rajasundaram, Jie Li, Blythe P. Durbin-Johnson, Zhong-Min Ma, Pabitra B. Pal, Danielle Beckman, Sean Ott, Reben Raeman, Jeffrey Lifson, John H. Morrison, Smita S. Iyer
Sonny R. Elizaldi, Chase E. Hawes, Anil Verma, Yashavanth Shaan Lakshmanappa, Ashok R. Dinasarapu, Brent T. Schlegel, Dhivyaa Rajasundaram, Jie Li, Blythe P. Durbin-Johnson, Zhong-Min Ma, Pabitra B. Pal, Danielle Beckman, Sean Ott, Reben Raeman, Jeffrey Lifson, John H. Morrison, Smita S. Iyer
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Research Article AIDS/HIV Inflammation

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

Abstract

CD4+ 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+ CD4+ T cells resembling lymph node central memory (TCM) cells. We observed chromatin accessibility at the CCR7, CD28, and BCL-6 loci, defining molecular features of TCM. Brain CCR7+ CD4+ 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 TCM cells in lymph nodes using FTY720 led to reduced CCR7+ CD4+ 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+ CD4+ T cells was observed, along with increased microglial activation and initiation of neurodegenerative pathways. Our findings highlight a role for CCR7+ CD4+ T cells in CNS immune surveillance, and their decline during chronic SIV highlights their responsiveness to neuroinflammation.

Authors

Sonny R. Elizaldi, Chase E. Hawes, Anil Verma, Yashavanth Shaan Lakshmanappa, Ashok R. Dinasarapu, Brent T. Schlegel, Dhivyaa Rajasundaram, Jie Li, Blythe P. Durbin-Johnson, Zhong-Min Ma, Pabitra B. Pal, Danielle Beckman, Sean Ott, Reben Raeman, Jeffrey Lifson, John H. Morrison, Smita S. Iyer

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Figure 6

CCR7+ CD4+ T cells in CNS exhibit functional TCM features and reside within skull BM.

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CCR7+ CD4+ T cells in CNS exhibit functional TCM features and reside wit...
(A) Representative gating for T cells within the skull BM and (B) corresponding frequencies of CD3+, CD4+ (top), CD8+ T cells, and CD4-to-CD8 ratios (bottom) across tissue compartments. (C) Population gates for CD4+ (purple) and CD8+ (green) subsets with (D) corresponding frequencies of CD28+ subsets across tissue compartments. (E) Phenotypic characterization of TCM-like (CCR7+; blue) and CD4+ TRM (CD69+; purple) cells from brain and skull BM. (F) Ki67 MFI and frequencies on CCR7– and CCR7+ CD4+ T cells after T cell activation using anti-CD3 and anti-CD28. (G–I) Representative gating for CD95+ CCR7+ CD4+ T cells and CD95+ CCR7–CD4+ T cells and bar charts illustrating cytokine production after stimulating with PMA/Ionomyocin in Brain, Skull BM, and Spleen. (I) Pie Charts indicating cytokine functionality after PMA/Ionomycin treatment. (A–F) Data points indicate individual tissue samples. (F) Symbols indicate skull BM (circle) or brain tissue (square) samples. Bars indicate medians. *P < 0.05, **P < 0.01, ***P < 0.001.