CCR7+ CD4 T Cell Immunosurveillance Disrupted in Chronic SIV-Induced Neuroinflammation in Rhesus Brain.

Elizaldi, S. R.; Hawes, C. E.; Verma, A.; Dinasarapu, A. R.; Lakshmanappa, Y. S.; Schlegel, B. T.; Rajasundaram, D.; Li, J.; Johnson, B. P. D.-; Ma, Z.-M.; Beckman, D.; Ott, S.; Lifson, J. D.; Morrison, J. H.; Iyer, S. S.

doi:10.1101/2023.08.28.555037

bioRxiv · 10.1101/2023.08.28.555037

CCR7+ CD4 T Cell Immunosurveillance Disrupted in Chronic SIV-Induced Neuroinflammation in Rhesus Brain.

Elizaldi, S. R.·Hawes, C. E.·Verma, A.·Dinasarapu, A. R.·Lakshmanappa, Y. S.·Schlegel, B. T.·Rajasundaram, D.·Li, J.·Johnson, B. P. D.-·Ma, Z.-M.·Beckman, D.·Ott, S.·Lifson, J. D.·Morrison, J. H.·Iyer, S. S.

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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 other 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 SIVCL57 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-induced neuroinflammation highlights their responsiveness to neuroinflammatory processes. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=87 SRC="FIGDIR/small/555037v1_ufig1.gif" ALT="Figure 1"> View larger version (20K): org.highwire.dtl.DTLVardef@191f9caorg.highwire.dtl.DTLVardef@a67d2dorg.highwire.dtl.DTLVardef@645443org.highwire.dtl.DTLVardef@d81fd6_HPS_FORMAT_FIGEXP M_FIG C_FIG In BriefUtilizing single-cell and spatial transcriptomics on adult rhesus brain, we uncover a unique CCR7+ CD4 T cell subset resembling central memory T cells (TCM) within brain and border tissues, including skull bone marrow. Our findings show decreased frequencies of this subset during SIV- induced chronic neuroinflammation, emphasizing responsiveness of CCR7+ CD4 T cells to CNS disruptions. HighlightsO_LICCR7+ CD4 T cells survey border and parenchymal CNS compartments during homeostasis; reduced presence of CCR7+ CD4 T cells in cerebrospinal fluid leads to immune activation, implying a role in neuroimmune homeostasis. C_LIO_LICNS CCR7+ CD4 T cells exhibit phenotypic and functional features of central memory T cells (TCM) including production of interleukin 2 and the capacity for rapid recall proliferation. Furthermore, CCR7+ CD4 T cells reside in the skull bone marrow. C_LIO_LICCR7+ CD4 T cells are markedly decreased within the brain parenchyma during chronic viral neuroinflammation. C_LI

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Elizaldi, S. R., Hawes, C. E., Verma, A., Dinasarapu, A. R., Lakshmanappa, Y. S., Schlegel, B. T., Rajasundaram, D., Li, J., Johnson, B. P. D.-, Ma, Z.-M., Beckman, D., Ott, S., Lifson, J. D., Morrison, J. H., Iyer, S. S.. 2023-08-31. CCR7+ CD4 T Cell Immunosurveillance Disrupted in Chronic SIV-Induced Neuroinflammation in Rhesus Brain.. https://doi.org/10.1101/2023.08.28.555037

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