PMN-MDSC Frequency Discriminates Active Versus Latent Tuberculosis and Could Play a Role in Counteracting the Immune-Mediated Lung Damage in Active Disease

Abstract

Tuberculosis (TB), due to Mycobacterium tuberculosis infection, is still the principal cause of death caused by a single infectious agent. The balance between the bacillus and host defense mechanisms reflects the different manifestations of the pathology. Factors defining this variety are unclear and likely involve both mycobacterial and immunological components. Myeloid derived suppressor cells (MDSC) have been shown to be expanded during TB, but their role in human TB pathogenesis is not clear. We evaluated the frequency of circulating MDSC by flow-cytometry in 19 patients with active TB, 18 with latent TB infection (LTBI), and 12 healthy donors (HD) as control. Moreover, we investigated the capacity of MDSC to modulate the mycobactericidal activity of monocytes. The association between MDSC level and TB chest X-ray severity score was analyzed. We observed that, unlike active TB, polymorphonuclear (PMN)-MDSC are not expanded in LTBI patients, and, by performing a receiver operating characteristic (ROC) curve analysis, we found that PMN-MDSC frequency supported the discrimination between active disease and LTBI. Interestingly, we observed an association between PMN-MDSC levels and the severity of TB disease evaluated by chest X-ray. Specifically, PMN-MDSC frequency was higher in those classified with a low/mild severity score compared to those classified with a high severity score. Moreover, PMN-MDSC can impact mycobacterial growth by inducing ROS production in Bacillus Calmette et Guerin (BCG)-infected monocytes. This effect was lost when tested with M. tuberculosis (MTB), In conclusion, our data indicate that the elevated frequency of PMN-MDSC in IGRA-positive individuals is associated with active TB. Our findings also pointed out a beneficial role of PMN-MDSC during human active TB, most likely associated with the limitation of inflammation-induced tissue damage.

Circulating Monocyte-Like Myeloid Derived Suppressor Cells and CD16 Positive Monocytes Correlate With Immunological Responsiveness of Tuberculosis Patients

“…On the contrary, HR-TB individuals displayed the highest percentages of PMN-MDSC ( Figure 2 ). These results are clearly in agreement with those recently described by Grassi et al where an association between PMN-MDSC levels and the severity of TB disease, evaluated by chest X-ray, was demonstrated ( Grassi et al., 2021 ). In that work, the authors show that the frequencies of PMN-MDSC are higher in those TB patients classified with a low/mild severity score compared to those classified with a high severity score.…”

“…In that work, the authors show that the frequencies of PMN-MDSC are higher in those TB patients classified with a low/mild severity score compared to those classified with a high severity score. However, it is important to mention that this classification criterion does not take into account immunological parameters ( Grassi et al., 2021 ). We also observed for the first time, that the frequencies of CD14 ++ CD16 + and CD14 + CD16 ++ monocytes and M-MDSC return close to healthy control levels after a short time of anti-TB treatment ( Figure 3 ).…”

“…MDSC described in TB mainly comprise two different subsets: monocyte-like MDSC (M-MDSC) and polymorphonuclear-like MDSC (PMN-MDSC) cells ( Bronte et al., 2016 ; Kotzé et al., 2020 ). Although no specific markers have been described for MDSC identification ( Magcwebeba et al., 2019 ), human M-MDSC were shown to express CD14, CD33, and CD11b with a lack of CD15 and low or no HLA-DR expression [CD11b + HLA-DR -/low (CD14 + )] ( Damuzzo et al., 2015 ; Bronte et al., 2016 ; Cassetta et al., 2019 ; Kotzé et al., 2020 ; Grassi et al., 2021 ). On the other hand, PMN-MDSC express CD15, CD33 and CD11b in the absence of CD14 and low or no HLA-DR expression [CD15 + (CD14 - CD11b + )] ( Damuzzo et al., 2015 ; Bronte et al., 2016 ; Cassetta et al., 2019 ; Kotzé et al., 2020 ; Grassi et al., 2021 ).…”

Myeloid-Derived Suppressor Cells Mediate T Cell Dysfunction in Nonhuman Primate TB Granulomas

“…The magnitude of suppressive effects of MDSCs on TILs has a direct correlation with proximal localization and physical engagement ( 22 ). Apart from cancer, transplantation, and inflammatory pathologies, where these cells are extensively studied ( 12 – 15 ), MDSCs have been recently reported to be abundant in the blood ( 7 , 23 , 24 ), pleural effusions ( 7 ), and bronchoalveolar lavage (BAL) fluid ( 23 ) of active TB (ATB) patients. MDSCs could potently impair adaptive immunity by killing DCs ( 25 ) or inhibiting T cell functions ( 7 , 9 , 10 , 22 , 25 – 35 ).…”

Immune Correlates of Non-Necrotic and Necrotic Granulomas in Pulmonary Tuberculosis: A Pilot Study

“…The role of MDSCs in TB progression is further confirmed by the abundance of MDSCs in mouse strains that are vulnerable to progressive disease, including the NOS2 −/− , C3HeB/FeJ, 129S2 strains, for which the highest levels were observed in immunodeficient (RAG2 −/− ) animals, when compared to TB resistant mice that are devoid of solid/non-necrotic granulomas [32]. Furthermore, the frequency of MDSCs circulating in the blood of TB patients correlates with the disease severity [13,[33][34][35]. While M-MDSCs constitute the significant subset of circulating MDSCs, accounting for 4% to 10% of the peripheral blood mononuclear cell (PBMC) fraction, the PMN-MDSC frequency can account for up to 30% of the total PBMCs of TB patients [13,20].…”