Peripheral Immune Remodeling After Spinal Cord Injury: Marked by Expansion of CD38+, CTLA-4+, and PD-1+ T and NK Cells

BACKGROUND AND OBJECTIVES: Spinal cord injury (SCI) is associated with severe immunologic changes, such as SCI-induced immune deficiency syndrome, which heightens susceptibility to infections. However, the immune components underlying this immune reorganization remain poorly defined. This study aimed to characterize immune remodeling in patients with SCI across different time points postinjury.

METHODS: High-dimensional flow cytometric profiling was performed on peripheral blood samples from patients with SCI in a cross-sectional observational study to assess immune changes at different postinjury time points. Patients in the subacute phase (22-67 days of postinjury [dpi]) and chronic phase (≥365 dpi) were compared with healthy, sex-matched, and age-matched controls.

RESULTS: Alterations in the T-cell and natural killer (NK) cell compartments were observed, particularly in the subacute phase postinjury. Memory T cells and NK cells showed elevated expression of the NAD+ metabolizing enzyme CD38 and immune checkpoint molecules, cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1), indicating immune activation and possible exhaustion. Coexpression of CD38 and CTLA-4 on T cells was rare, suggesting distinct activation and inhibitory states. In chronic patients, we observed decreased frequencies of NK cells with no substantial changes in T cells and B cells. Notably, changes in CD38, CTLA-4, and PD-1 were no longer found in patients in the chronic phase.

DISCUSSION: These findings reveal noteworthy changes in immune cell activation and exhaustion markers that may contribute to immune vulnerability after SCI, offering novel insights into potential therapeutic targets, such as NAD+ metabolism and immune checkpoint modulation.