T-cell deficiency and hyperinflammatory monocyte responses associate with Mycobacterium avium complex lung disease

Abstract

Immunological mechanisms of susceptibility to nontuberculous mycobacterial (NTM) disease are poorly understood. To understand NTM pathogenesis, we evaluated innate and antigen-specific adaptive immune responses to Mycobacterium avium complex (MAC) in asymptomatic individuals with a previous history of MAC lung disease (MACDZ). We hypothesized that Mav-specific immune responses are associated with susceptibility to MAC lung disease. We measured MAC-, NTM-, or MAC/Mtb-specific T-cell responses by cytokine production, expression of surface markers, and analysis of global gene expression in 27 MACDZ individuals and 32 healthy controls. We also analyzed global gene expression in Mycobacterium avium-infected and uninfected peripheral blood monocytes from 17 MACDZ and 17 healthy controls. We were unable to detect increased T-cell responses against MAC-specific reagents in MACDZ compared to controls, while the responses to non-mycobacteria derived antigens were preserved. MACDZ individuals had a lower frequency of Th1 and Th1* T-cell populations. In addition, MACDZ subjects had lower transcriptional responses in PBMCs stimulated with a mycobacterial peptide pool (MTB300). By contrast, global gene expression analysis demonstrated upregulation of proinflammatory pathways in uninfected and M. avium-infected monocytes, i.e. a hyperinflammatory in vitro response, derived from MACDZ subjects compared to controls. Together, these data suggest a novel immunologic defect which underlies MAC pathogenesis and includes concurrent innate and adaptive dysregulation which persists years after completion of treatment.

Impact of aging on the immunological and microbial landscape of the lung during non-tuberculous mycobacterial infection

“…On the other hand, expression of genes important for antigen presentation, co-stimulation of T cells, and type II IFN signaling were upregulated in young animals. Collectively, these data indicate a dysregulation of anti-microbial function with age in lung resident macrophages [88].…”

“…Interestingly, the frequency of MAC-specific CD4 T cells was higher in the left lung. This response was dominated by IFNγ and TNFα while IL-17 producing CD4 T cells were not consistently detected in either lung [88]. In contrast, MAC-specific CD8 T cell responses were larger in the right lung compared to the left lung and were more significant in the young animals compared to the aged.…”

Multiparameter immunoprofiling for the diagnosis and differentiation of progressive versus nonprogressive nontuberculous mycobacterial lung disease–A pilot study

“…In contrast to crude M. tb lysate, or culture filtrate proteins, MTB300 contains equimolar concentrations of peptides which are efficiently processed and presented by antigen-presenting cells. This MTB300 peptide megapool contains a mixture of 300 M. tb derived T cell epitopes from 90 M. tb proteins that specifically targets a large fraction of M. tb-specific CD4 + and probably CD8 + T cells, which can share epitopes with NTM species [31,32]. In our study, the overall response against PPD and MTB300 was higher in patients with progressive versus nonprogressive NTM-LD, possibly representing a higher antigen encounter by CD8 + T-cells in peripheral blood associated with more progressive forms of NTM-LD.…”

“…We previously reported that a non-cytokine activation immunoassay strategy was able to differentiate latent TB patients from TB-uninfected controls and potentially infer risk of TB reactivation by predictive modeling [12]. Recently, Lindestam Arlehamn CS et al, also reported that MAC-PD patients showed significantly increased MTB300-specific CD134 + PD-L1 + co-expression in T-cells compared to QFT-positive controls [32]. In line with these studies, patients with progressive NTM-LD had a higher frequency of CD8 T-cells co-expressing CD25 + CD134 + compared with patients with nonprogressive NTM-LD.…”

The MegaPool Approach to Characterize Adaptive CD4+ and CD8+ T Cell Responses

“…In addition to being used primarily for the characterization of human CD4+ T cell reactivity, this pool has also been used, based on the similarity of peptide binding repertoires, to probe reactivity in non‐human primates (Foreman et al., 2022; Kauffman et al., 2021; Mothe et al., 2015; Sakai et al., 2021; White et al., 2021; Wood et al., 2020) and mice (Patankar et al., 2020). Additional MPs were designed to explore the relationship with conservation in other Mycobacteria (Lindestam Arlehamn et al., 2022), to perform a quantitative analysis of TCR and epitope repertoire composition (Glanville et al., 2017; Scriba et al., 2017), to study specific gene deficiencies in humans (Kong et al., 2018; Martinez‐Barricarte et al., 2018), to study the role of CD8+ T cell responses (Pomaznoy et al., 2020), and to derive immune signatures associated with transcriptional profiles and different disease outcomes (Singhania, Dubelko, et al., 2021).…”