Clonally expanded, targetable, natural killer-like NKG7 T cells seed the aged spinal cord to disrupt myeloid-dependent wound healing

Guiping Kong; Yayue Song; Yuyang Yan; Samantha M Calderazzo; Madhu Sudhana Saddala; Fabian De Labastida Rivera; Jonathan D Cherry; Noah Eckman; Eric A Appel; Adam Velenosi; Vivek Swarup; Riki Kawaguchi; Susanna S Ng; Brian K Kwon; David Gate; Christian R Engwerda; Luming Zhou; Simone Di Giovanni

doi:10.1016/j.neuron.2024.12.012

Clonally expanded, targetable, natural killer-like NKG7 T cells seed the aged spinal cord to disrupt myeloid-dependent wound healing

Neuron. 2025 Jan 9:S0896-6273(24)00911-5. doi: 10.1016/j.neuron.2024.12.012. Online ahead of print.

Authors

Guiping Kong¹, Yayue Song¹, Yuyang Yan¹, Samantha M Calderazzo², Madhu Sudhana Saddala³, Fabian De Labastida Rivera⁴, Jonathan D Cherry², Noah Eckman⁵, Eric A Appel⁵, Adam Velenosi⁶, Vivek Swarup³, Riki Kawaguchi⁷, Susanna S Ng⁸, Brian K Kwon⁹, David Gate¹⁰, Christian R Engwerda⁴, Luming Zhou¹¹, Simone Di Giovanni¹²

Affiliations

¹ Molecular Neuroregeneration, Division of Neuroscience, Department of Brain Sciences, Imperial College London, London, UK.
² Department of Pathology and Laboratory Medicine, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA; Boston University Alzheimer's Disease and CTE Centers, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA.
³ Department of Neurobiology and Behaviour, School of Biological Sciences, University of California Irvine, Irvine, CA, USA.
⁴ QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.
⁵ Department of Chemical Engineering, Stanford University, Stanford, CA, USA; Department of Materials Science & Engineering, Stanford University, Stanford, CA, USA; Department of Bioengineering, Stanford University, Stanford, CA, USA; Department of Paediatrics, Endocrinology, Stanford University, Stanford, CA, USA; ChEM-H Institute, Stanford University, Stanford, CA, USA; Woods Institute for the Environment, Stanford University, Stanford, CA, USA.
⁶ International Collaboration on Repair Discoveries, University of British Columbia, Vancouver, BC, Canada; Praxis Spinal Cord Institute, Vancouver, BC, Canada.
⁷ Program in Neurogenetics, Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA; Semel Institute for Neuroscience and Human Behaviour, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
⁸ QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia; Institute of Experimental Oncology, Medical Faculty, University Hospital Bonn, University of Bonn, Bonn, Germany.
⁹ International Collaboration on Repair Discoveries, University of British Columbia, Vancouver, BC, Canada; Department of Orthopaedics, University of British Columbia, Vancouver, BC, Canada.
¹⁰ The Ken & Ruth Davee Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
¹¹ Molecular Neuroregeneration, Division of Neuroscience, Department of Brain Sciences, Imperial College London, London, UK; Precision Research Center for Refractory Diseases, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 201620, China. Electronic address: l.zhou13@imperial.ac.uk.
¹² Molecular Neuroregeneration, Division of Neuroscience, Department of Brain Sciences, Imperial College London, London, UK. Electronic address: s.di-giovanni@imperial.ac.uk.

PMID: 39809279
DOI: 10.1016/j.neuron.2024.12.012

Abstract

Spinal cord injury (SCI) increasingly affects aged individuals, where functional impairment and mortality are highest. However, the aging-dependent mechanisms underpinning tissue damage remain elusive. Here, we find that natural killer-like T (NKLT) cells seed the intact aged human and murine spinal cord and multiply further after injury. NKLT cells accumulate in the spinal cord via C-X-C motif chemokine receptor 6 and ligand 16 signaling to clonally expand by engaging with major histocompatibility complex (MHC)-I-expressing myeloid cells. NKLT cells expressing natural killer cell granule protein 7 (Nkg7) disrupt myeloid-cell-dependent wound healing in the aged injured cord. Nkg7 deletion in mice curbs NKLT cell degranulation to normalize the myeloid cell phenotype, thus promoting tissue repair and axonal integrity. Monoclonal antibodies neutralizing CD8⁺ T cells after SCI enhance neurological recovery by promoting wound healing. Our results unveil a reversible role for NKG7⁺CD8⁺ NKLT cells in exacerbating tissue damage, suggesting a clinically relevant treatment for SCI.

Keywords: CD8(+) T cells; NKG7; NKLT cells; aging; granzyme K; regeneration; repair; spinal cord injury; wound healing.