Amyotrophic lateral sclerosis (ALS) is a non-neuron-autonomous disease where peripheral immune dysregulation significantly impacts disease progression. However, the immunopathological mechanisms of natural killer (NK) cells in ALS remain largely unexplored. This study enrolled 241 ALS patients and 102 healthy controls (HC), analyzing lymphocyte subsets, including T cells, B cells, and NK cells. A sub-cohort of 81 ALS patients was followed up for one year at three-month intervals. Linear mixed and Cox proportional hazards models were used to evaluate the association between lymphocyte subsets and ALS progression and prognosis. Our results revealed significant reductions in total T cells, helper T cells (Th), and NK cells in ALS patients compared to HC (P &;lt 0.05). Slow-progressing ALS patients exhibited higher counts of total T cells, Th, CD16-CD56 NK cells, and CD16CD56 NK cells, while showing lower counts of CD16CD56 NK cells compared to fast-progressing ALS patients (P &;lt 0.05). ALS patients with lower CD16CD56 NK cell counts experienced a faster decline in motor function than those with higher counts (P &;lt 0.05). Elevated CD16CD56 NK cell counts were associated with improved ALS prognosis (HR, 0.73; 95% CI: 0.60-0.90; P &;lt 0.05). This study suggests that CD16CD56 NK cells play a protective role in ALS progression and prognosis, offering a potential therapeutic target for ALS.
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