Abstract
BackgroundThe incidence of nontuberculous mycobacterial lung disease (NTM-LD) is increasing worldwide. Immune exhaustion has been reported in NTM-LD, but T-cell immunoglobulin and mucin domain-containing protein 3 (TIM3), a co-inhibitory receptor on T cells, has been scarcely studied.MethodsPatients with NTM-LD and healthy controls were prospectively recruited from July 2014 to August 2019 at three tertiary referral centers in Taiwan. We examined TIM3 expression on the T cells from the participants using flow cytometry. TIM3 expression was analyzed for different disease statuses and after treatment. The apoptosis and cytokine profiles were analyzed according to the TIM3 expression.ResultsAmong enrolled subjects (47 patients and 46 controls), TIM3 on CD4+ cells (6.44% vs. 4.12%, p = 0.028) and CD8+ cells (18.47% vs. 9.13%, p = 0.003) were higher in NTM-LD patients than in the controls. The TIM3 level on CD4+ and CD8+ T cells was positively associated with T-cell apoptosis in the NTM-LD patients. In stimulating peripheral blood mononuclear cells using PMA plus ionomycin, a high TIM3 level on T cells correlated with low interleukin-2 and tumor necrosis factor-alpha (TNF-α) on CD4+ cells and interferon-gamma and TNF-α on CD8+ T cells. For clinical manifestation, low body mass index (BMI), positive sputum acid-fast smear, and high radiographic score correlated with high TIM3 expression on T cells. After NTM treatment, TIM3+ decreased significantly on CD4+ and CD8+ T cells.ConclusionsIn patients with NTM-LD, TIM3+ expression increased over CD4+ and CD8+ T cells and correlated with cell apoptosis and specific cytokine attenuation. Clinically, TIM3+ T cells increased in patients with low BMI, high disease extent, and high bacilli burden but decreased after treatment.
Highlights
The incidence of nontuberculous mycobacteria lung disease (NTMLD) has increased over the last two decades and become an important clinical issue [1, 2]
Because previous studies showed that healthy controls had response to the NTM antigen [10, 18, 19] and we aimed to investigate the general effect of T-cell immunoglobulin and mucin domain-containing protein 3 (TIM3) functional blocking on apoptosis occurrence, we enrolled Mycobacterium avium complex (MAC)-LD patients and the healthy controls for the assay
We enrolled a total of 93 participants for baseline TIM3 examination, including 47 patients with MAC-LD and 46 controls
Summary
The incidence of nontuberculous mycobacteria lung disease (NTMLD) has increased over the last two decades and become an important clinical issue [1, 2]. Less than half of patients with positive sputum cultures for MAC and MAB clinically have the disease [6, 7], indicating the importance of host vulnerability to NTM pulmonary infection [8]. Our previous report showed that programmed death-1 (PD-1), a suppressive coreceptor for T-cell activation [11], was increased on lymphocytes in patients with MAC-LD and might play an essential role in attenuating host immunity [10]. The role of the TIM3 pathway in modulating T-cell immune responses has been scarcely studied in NTM-LD in terms of clinical manifestation and cellular function. Immune exhaustion has been reported in NTM-LD, but T-cell immunoglobulin and mucin domain-containing protein 3 (TIM3), a co-inhibitory receptor on T cells, has been scarcely studied
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