The role of increasing TIM3 on T cells in patients with nontuberculous mycobacterial lung disease: from immune cell dysfunction to clinical severity

Abstract

Background: Nontuberculous mycobacterial lung disease (NTM-LD) is increasing worldwide but the nature remains unclear. The immune exhaustion has been reported and T cell immunoglobulin and mucin domain- containing protein 3 (TIM3) is reported as a new “co- inhibitory” receptor. But there are scarce studies investigating the role of TIM3 in NTM-LD.

Methods: We prospectively recruited patients with NTM-LD in multi-centers in Taiwan and excluded patients with HIV infection. We examined the TIM3 expression on T cell using flow cytometry and checked single nucleotide polymorphism (SNP) of TIM3 gene by Agena MassARRAY platform.

Results: Among enrolled subjects (48 patients and 46 controls), TIM3 on CD4 cells (6.39% vs 4.12%, p=0.028) and CD8 cells (19.80% vs 9.74%, p=0.007) were significantly higher in patients with NTM-LD than that in the controls. The TIM3 level on T cells were significantly associated with T cell apoptosis and in-vitro stimulation showed that TIM3 were induced to increase both CD4+ and CD8+ T cells. In addition, the post-stimulation TIM3 level was negatively correlated with tumor necrosis factor-alpha (TNF-α) on CD8+ T cells. For clinical manifestation, TIM3 on CD4 cells was associated with fibro-cavitary pattern and positive sputum acid-fast smear (all p<0.05). We examined the SNPs of TIM3 gene and found a SNP “X” was associated NTM-LD significantly (odds ratio: 1.63, 95% C.I.:1.07-2.49).

Conclusions: TIM3 on T cells were increasing in NTM-LD and correlated with apoptosis and attenuation of TNF-α. In addition, TIM3 correlates with cavitary pattern and high bacilli burden. A TIM3 SNP might involve NTM-LD pathogenesis.