Grace Newman

Background: Spinal cord injury (SCI) results in impairments in the connectivity between the cerebral cortex, brainstem, and spinal cord neurons due to the disruption of ascending and descending neural pathways, leading to a loss of sensory-motor functions.¹ SCI affects about 265,000 people in the U.S., with 12,000 new cases annually.¹ It is considered a complex, progressive, and incurable condition.¹ The innate immune response has been proven to impact the injury response. However, the effects of the adaptive immune response are much less studied.^2,3 Recent research has been testing the efficacy of new combinations of regimens to combat SCI inflammation.³ The results from these trials demonstrated that therapeutically controlling the inflammatory response after an SCI can reduce secondary injury, restore the function of nerves, and improve patient prognosis and quality of life.³ Recent studies discussed in this review have started to explore new potential mechanisms to target future T-cell therapies for SCI³. The mechanisms include restrained local inflammation promoted by CD4+ T cells, dampening microglial activation and microglia-mediated demyelination by regulatory T-cells (Tregs), disruption of myeloid-cell mediated wound healing by natural killer-like T-cells (NKLT), and increased neuroinflammation mediated by conventional type-1 dendritic cells  (cDC1s).^4,5,2,6 Targeting any of these mechanisms could be a viable option for promoting functional recovery in SCI patients.

Research Objectives:  The goal of this literature review is to discuss mechanisms by which T-cell involvement impacts spinal cord injury recovery.

Methods:  An online search in the PubMed database was conducted from 2017 to 2025 using the following keywords: “spinal cord injury,” “spinal cord injury treatment,” and “immunity,” as well as the MeSH term “spinal cord injuries.”

Results:  One study engineered a self-reactive, T-cell receptor (TCR)-based CD4+ T-cell therapy for SCI that was found to reduce secondary neuronal degeneration and improve functional recovery by limiting local inflammation.⁴ Another study found that Tregs drive the microglia-mediated downregulation of the apolipoprotein D (ApoD) gene, thereby decreasing the production of proinflammatory cytokines.⁵ Tregs are also involved in suppressing the signal transducer and activator of transcription (STAT3), which impairs functional recovery in many neuroinflammatory diseases.⁵ Together, these functions promote functional recovery after SCI by decreasing microglial activation and demyelination.⁵ A third study found that natural killer cell granule protein 7 (NKG7)+CD8+ NKLT cells degranulate granzyme K, which disrupts myeloid cell-mediated wound healing and exacerbates injury.² Deleting the Nkg7 gene in mice reduced NKLT degranulation, normalizing the immune environment and promoting tissue repair and axonal preservation.² The final study discovered that depletion of cDC1s or pharmacological blockade of T-cell egress from lymph nodes reduced CD8+ T cell activity and improved locomotor function in SCI mice.⁶

Conclusion:  Targeting T-cell mechanisms with a variety of approaches could be a viable way to promote functional recovery in SCI patients. Potential therapies include a self-reactive, TCR-based CD4+ T cell therapy, CNS antibody-mediated depletion of CD8+ NKLT cells, Nkg7 deletion, reducing NKLT cell degranulation, upregulation of Tregs, targeting the STAT3 pathway, cDC1 depletion, or targeting T-cell egress.^4,2,5,6 Future studies could examine precisely how NKG7 is cytotoxic and leads to degranulation or identify common target antigens of T-cells in SCI.^2,4 Further research is required to examine the viability of these options in treating human SCI, but mouse models are already showing promising leads.

Work Cited:

1. Yari D, Saberi A, Salmasi Z, et al. Recent Advances in the Treatment of Spinal Cord Injury. Arch Bone Jt Surg. 2024;12(6):380-399. doi:10.22038/ABJS.2023.73944.3424
2. Kong G, Song Y, Yan Y, et al. Clonally expanded, targetable, natural killer-like NKG7 T cells seed the aged spinal cord to disrupt myeloid-dependent wound healing. 2025;113(5):684-700.e8. doi:10.1016/j.neuron.2024.12.012
3. Ren D, Li H, Liu X, Wang M. Clinical Efficacy of Ganglioside Combined with Methylprednisolone in the Treatment of Spinal Cord Injury and Its Effect on Inflammatory Response and Oxidative Stress Factors. J Coll Physicians Surg Pak. 2025;35(2):238-241. doi:10.29271/jcpsp.2025.02.238
4. Gao W, Kim MW, Dykstra T, et al. Engineered T cell therapy for central nervous system injury. 2024;634(8034):693-701. doi:10.1o038/s41586-024-07906-y
5. Liu R, Li Y, Wang Z, et al. Regulatory T cells promote functional recovery after spinal cord injury by alleviating microglia inflammation via STAT3 inhibition. CNS Neurosci Ther. 2023;29(8):2129-2144. doi:10.1111/cns.14161
6. Wang LQ, Wang XY, Ma YH, Zhou HJ. Conventional type 1 dendritic cells in the lymph nodes aggravate neuroinflammation after spinal cord injury by promoting CD8+ T cell expansion. Mol Med. 2025;31(1):37. Published 2025 Feb 3. doi:10.1186/s10020-024-01059-4