T cell exhaustion in the peripheral blood of patients with sporadic lymphangioleiomyomatosis

Lymphangioleiomyomatosis (LAM) is a rare, progressive neoplastic lung disease. Lymphocytes play a central role in tumor immunity. However, circulating lymphocyte count and function have not been studied yet in sporadic LAM. Two-sample Mendelian randomization (TSMR) analysis was used to estimate the causal effect of circulating lymphocyte count on sporadic LAM. Circulating lymphocyte subsets were quantified, and inhibitory receptors (PD-1, LAG-3, TIM-3, and CTLA-4) on T cells were measured in a clinical cohort. CD4⁺ and CD8⁺ T cells were isolated and cultured to measure cytokine expression including IFN-γ and IL-4, followed by PD-1 blockade experiments using an anti-PD-1 antibody. TSMR analysis showed lower circulating lymphocyte count was associated with a higher risk of sporadic LAM. Circulating lymphocytes, mainly T cells instead of B and NK cells, were significantly decreased in sporadic LAM. Reduced CD8⁺ T cell count was significantly correlated with VEGF-D, CT gradings and FEV 1 % pred. The expression of PD-1, but not LAG-3, TIM-3, or CTLA-4, was significantly increased on both CD4⁺ and CD8⁺ T cells. The frequency of IFN-γ but not IL-4 producing CD4⁺ and CD8⁺ T cells was significantly decreased in sporadic LAM. PD-1 blockade restored the frequency of IFN-γ producing CD4⁺ and CD8⁺ T cells at least in part. Our data indicate that circulating lymphocytes, mainly T cells, are associated with the development of sporadic LAM. T cell exhaustion occurs in the peripheral blood of patients with this disease. Immune checkpoint blockade therapy may be a new strategy for sporadic LAM.