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

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.

Characteristics of Circulating CD4+ T Cell Subsets in Patients with Mycobacterium avium Complex Pulmonary Disease

“…It was recently shown that in vitro blockade of PD-1 signaling enhanced MAC-specific IFN-γ production by T cells [25] and NK T cells of PTB patients [42], indicating that this inhibitory pathway also affects T cell functions during mycobacterial infection. Elevated CTLA-4 was also observed on CD4 + T cells in NTM infection [24]. Consistent with these reports, we found that PD-1 + CD4 + T cells and CTLA-4 + CD4 + T cells were more prevalent in patients with MAC-PD compared with that in control participants.…”

“…Antigen-stimulated blood cells from NTM-PD patients showed an elevated Treg population compared with that from control individuals [39]. Furthermore, Tregs were increased in the peripheral blood of cystic fibrosis NTM patients compared with that of controls [24]. Our study demonstrates that Tregs were increased in MAC-stimulated PBMCs of MAC-PD patients compared with that of control individuals, suggesting that the elevated levels of Tregs might suppress T-cell responses, thereby protecting MAC and playing a pathogenic role in MAC-PD.…”

“…Additionally, these receptors play an important role in T cell dysfunction during chronic mycobacteria infections such as TB [21][22][23]. However, there are only a few reports addressing the role of PD-1 and CTLA-4 pathways, especially in MAC-PD [24,25].…”

The Rise of Non-Tuberculosis Mycobacterial Lung Disease

“…A more comprehensive study, that used multiplexed bead-based assays to evaluate 22 cytokines in 24 MABS patients, showed reduced levels of IFNγ, IL-12, IL-4, and IL-13 and high levels of IL-17 and IL-23 in patients. A hi-dimensional flow analysis between individuals at risk and not at risk of MABS disease revealed immune exhaustion in T cells (CTLA-4) may be playing a role (98). These finding is similar to studies performed in MAC infection (93,95).…”

“…Research priorities recommended in the US and UK include rapid diagnostic tools fast identification of infecting species (34) and simple and cheap screening tool to identify patients at risk (83,98,112). These are considered high impact research goals that would alert clinicians to at risk patients enabling faster initiation of appropriate treatment and ultimately, superior care.…”