Anomalies in T Cell Function Are Associated With Individuals at Risk of Mycobacterium abscessus Complex Infection.

Viviana P Lutzky,Andreas Kupz,Scott C Bell,Daniel J Smith,Champa N Ratnatunga,Denise L Doolan,Rachel M Thomson,John J Miles,David W Reid

doi:10.3389/fimmu.2018.01319

Abstract

The increasing global incidence and prevalence of non-tuberculous mycobacteria (NTM) infection is of growing concern. New evidence of person-to-person transmission of multidrug-resistant NTM adds to the global concern. The reason why certain individuals are at risk of NTM infections is unknown. Using high definition flow cytometry, we studied the immune profiles of two groups that are at risk of Mycobacterium abscessus complex infection and matched controls. The first group was cystic fibrosis (CF) patients and the second group was elderly individuals. CF individuals with active M. abscessus complex infection or a history of M. abscessus complex infection exhibited a unique surface T cell phenotype with a marked global deficiency in TNFα production during mitogen stimulation. Importantly, immune-based signatures were identified that appeared to predict at baseline the subset of CF individuals who were at risk of M. abscessus complex infection. In contrast, elderly individuals with M. abscessus complex infection exhibited a separate T cell phenotype underlined by the presence of exhaustion markers and dysregulation in type 1 cytokine release during mitogen stimulation. Collectively, these data suggest an association between T cell signatures and individuals at risk of M. abscessus complex infection, however, validation of these immune anomalies as robust biomarkers will require analysis on larger patient cohorts.

Highlights

Pulmonary infection caused by non-tuberculous mycobacteria (NTM) is an emerging threat with serious public health consequences
We first investigated the phenotypic and functional immune profiles of Peripheral blood mononuclear cells (PBMC) in cystic fibrosis (CF) patients to probe for functional deficiencies that could underlie predisposition to NTM infection
Cohorts were categorized as CF with active NTM infection (CFAct), CF with a past history of NTM infection (CFPast), CF with chronic Pseudomonas aeruginosa (Pa) infection and healthy controls (HCA), all matched in both age (ANOVA P = 0.350) and gender distribution (Chi-square P = 0.445)

Summary

INTRODUCTION

Pulmonary infection caused by non-tuberculous mycobacteria (NTM) is an emerging threat with serious public health consequences. Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), programmed cell death protein 1 (PD-1), and T-cell immunoglobulin domain and mucin domain 3 (TIM-3) are negative regulatory check points that are important for T cell tolerance and regulation during the immune response Known for their use as targets in cancer immunotherapy [22], these immune checkpoints have been shown to play an important role in T cell exhaustion during chronic infections such as TB [23,24,25,26,27]. The first group was CF patients and the second group was immunocompetent middle aged to elderly patients with MABS infection We show across both groups abnormalities in global T cell function that associate with individuals at risk of infection. Polyfunctionality analysis was performed using Pestle and SPICE V53 [34]

RESULTS

DISCUSSION

ETHICS STATEMENT