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

• Published in: The Journal of clinical investigation Vol. 134; no. 9; pp. 1 - 19
• Main Authors: Elizaldi, Sonny R, Hawes, Chase E, Verma, Anil, Shaan Lakshmanappa, Yashavanth, 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: Journal Article
• Language: English
• Published: United States American Society for Clinical Investigation 01.05.2024
• Subjects: Animals; Antigens; Antiretroviral therapy; Bcl-6 protein; Bone marrow; Brain - immunology; Brain - metabolism; Brain - pathology; Brain - virology; CC chemokine receptors; CD28 antigen; CD4 antigen; CD4-Positive T-Lymphocytes - immunology; Cell cycle; Cell proliferation; Cerebrospinal fluid; Chromatin; Chronic infection; Cytokines; Flow cytometry; FTY720; Gene expression; HIV; Homeostasis; Human immunodeficiency virus; Immunologic Surveillance; Immunosurveillance; Inflammation; Interleukin 2; Lymph nodes; Lymphocytes; Lymphocytes T; Macaca mulatta; Memory cells; Monocytes; Neuroinflammatory Diseases - immunology; Neuroinflammatory Diseases - pathology; Receptors, CCR7 - genetics; Receptors, CCR7 - immunology; Receptors, CCR7 - metabolism; Simian Acquired Immunodeficiency Syndrome - drug therapy; Simian Acquired Immunodeficiency Syndrome - immunology; Simian Immunodeficiency Virus - immunology; Spleen; T cell receptors; Transcriptomics; AIDS/HIV; Adaptive immunity; Inflammation; T cells; Neurological disorders
• ISSN: 1558-8238; 0021-9738; 1558-8238
• DOI: 10.1172/JCI175332

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.