Pulmonary infections caused by nontuberculous mycobacteria (NTM) are increasing in incidence worldwide in both the immune-compromised and immune-competent. Mycobacterium avium complex (MAC) and Mycobacterium abscessus (MABS) are the most common causative organisms globally. Our aim was to determine immune correlates of disease during different stages of this emerging infectious threat. A total of 95 subjects were enrolled. Patient groups included pre-treatment patients with MAC/MABS infection, post treatment patients in disease remission, patients with persistent MAC/MABS infection despite therapy and control groups consisted of patients with bronchiectatic lung disease but no history of NTM disease and matched healthy controls. Peripheral blood mononuclear cells were phenotyped by <18-parameter flow panels. Gene expression in CD4+ and CD8+ T cells populations were digitally quantified by NanoString technology. Patients with active infection with MAC and MABS showed specific T cell gene modules triggered by NTM infection as well as specific gene expression patterns that were unique to each species. A gradual change of gene expression towards control levels was seen after treatment. However patients with persistent infection had a gene signature most similar to controls indicating “immune blindness” in persistent infection, the signature of which can be identified in peripheral blood. Differential abundance of central memory and effector memory CD4+ T cells and CD8+ effector cells was seen across groups with both disease and species-specific patterns. These cells differed both in abundance and in expression of immune checkpoints CTLA4 and PD1 while TIM3 remained unchanged. Cytokine response to mitogens revealed dysfunction in IFNγ, TNFα secretion in active infection as well as impaired polyfuntionality in persistent infection. Collectively, these findings both enhance the understanding of the underlying pathomechanisms of NTM lung disease and may lead to development of biomarkers for active disease, infecting species, progression and/or remission of disease and greatly informed therapeutic treatment.