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Hierarchical gating strategy used to identify ILC populations in mouse lungs a–c, C57BL/6 mice were aerosol infected with approximately 100 CFU Mtb and lungs were collected at different d.p.i. and flow cytometry analysis was carried out on single-cell suspensions. a, b, Flow gating strategies for ILC1s (CD45⁺CD127⁺Lin⁻NKp46⁺NK1.1⁺), ILC2s (CD45⁺CD127⁺Lin⁻NK1.1⁻Sca1⁺) and ILC3 (CD45⁺CD127⁺Lin⁻NK1.1⁻Rorγt⁺) and NKp46-expressing (CD45⁺CD127⁺Lin⁻NK1.1⁻Rorγt⁺NKp46⁺) ILC3s are shown. c, Rorγt–GFP mice were aerosol-infected with approximately 100 CFU Mtb and lungs were collected at 14 d.p.i. ILC3 (CD45⁺CD127⁺Lin⁻NK1.1⁻GFP⁺) populations were quantified using flow cytometry.
Source publication
Tuberculosis is the leading cause of death by an infectious disease worldwide¹. However, the involvement of innate lymphoid cells (ILCs) in immune responses to infection with Mycobacterium tuberculosis (Mtb) is unknown. Here we show that circulating subsets of ILCs are depleted from the blood of participants with pulmonary tuberculosis and restored...
Citations
... The expression of the CXCR5 receptor for CXCL13 was also increased in patients with active TB, suggesting that the CXCL13-CXCR5 axis may promote ILC3 activity after M.tb infection. Moreover, the addition of WT ILC3 infected M.tb restored early M.tb clearance in Rag2-/-IL2r-γ-/-mice, suggesting that harnessing the efficacy of ILC3s may be a novel pathway to induce TB control through Th17 immunity [26]. Reports suggest that Th17 immunity, which includes the effector cytokines IL-17, IL-22, and IL-23, might have a protective effect in M.tb infections, as shown in several animal studies [48][49][50][51]. ...
Over the past decade, a group of lymphocyte-like cells called innate lymphoid cells (ILCs) has gained considerable attention due to their crucial role in regulating immunity and tissue homeostasis. ILCs, lacking antigen-specific receptors, are a group of functionally differentiated effector cells that act as tissue-resident sentinels against infections. Numerous studies have elucidated the characteristics of ILC subgroups, but the mechanisms controlling protective or pathological responses to pathogens still need to be better understood. This review summarizes the functions of ILCs in the immunology of infections caused by different intracellular and extracellular pathogens and discusses their possible therapeutic potential.
... IL-22 induces the production of several anti-bacterial peptides and activation of macrophages to better control mycobacterial infections [26]. In mice, IL-23-dependent expansion of Type 3 innate lymphoid cells (ILC3s) and production of IL-17 and IL-22 were found to be critical inducers of lung CXC motif chemokine ligand 13 (CXCL13), early innate immunity and the formation of protective lymphoid follicles within granulomas [27]. However, Th1 and Th17 cross-regulation is essential for an optimized response against M. tuberculosis. ...
Tuberculosis has a major global impact. Immunocompetent hosts usually control this disease, resulting in an asymptomatic latent tuberculosis infection (LTBI). Because TNF inhibitors increase the risk of tuberculosis reactivation, current guidelines recommend tuberculosis screening before starting any biologic drug, and chemoprophylaxis if LTBI is diagnosed. Available evidence from clinical trials and real-world studies suggests that IL-17 and IL-23 inhibitors do not increase the risk of tuberculosis reactivation.
To evaluate psoriasis patients with treated or untreated newly diagnosed LTBI who received IL-17 and IL-23 inhibitors and the tolerability/safety of tuberculosis chemoprophylaxis.
This is a retrospective, observational, multinational study from a series of 14 dermatology centres based in Portugal, Spain, Italy, Greece and Brazil, which included adult patients with moderate-to-severe chronic plaque psoriasis and newly diagnosed LTBI who were treated with IL-23 or IL-17 inhibitors between January 2015 and March 2022. LTBI was diagnosed in the case of tuberculin skin test and/or interferon gamma release assay positivity, according to local guideline, prior to initiating IL-23 or IL-17 inhibitor. Patients with prior diagnosis of LTBI (treated or untreated) or treated active infection were excluded.
A total of 405 patients were included; complete/incomplete/no chemoprophylaxis was administered in 62.2, 10.1 and 27.7% of patients, respectively. The main reason for not receiving or interrupting chemoprophylaxis was perceived heightened risk of liver toxicity and hepatotoxicity, respectively. The mean duration of biological treatment was 32.87 ± 20.95 months, and only one case of active tuberculosis infection (ATBI) was observed, after 14 months of treatment with ixekizumab. The proportion of ATBI associated with ixekizumab was 1.64% [95% confidence interval (CI): 0–5.43%] and 0% for all other agents and 0.46% (95% CI 0–1.06%) and 0% for IL-17 and IL-23 inhibitors, respectively (not statistically significant).
The risk of tuberculosis reactivation in patients with psoriasis and LTBI does not seem to increase with IL-17 or IL-23 inhibitors. IL-17 or IL-23 inhibitors should be preferred over TNF antagonists when concerns regarding tuberculosis reactivation exists. In patients with LTBI considered at high risk for developing complications related to chemoprophylaxis, this preventive strategy may be waived before initiating treatment with IL-17 inhibitors and especially IL-23 inhibitors.
... Thus, ILCs may reflect functional continua and appear as transition cell types [30,31]. Current strategies rely on negative selection of ILCs, sorted by the lack of lineage-defining surface markers and by the expression of IL-7Rα, CD90, and CD49a [2,[92][93][94][95]. However, canonical ILC markers such as CD90 and IL-7R are subject to regulation and thus not constantly expressed on the surface of intestinal or pulmonary ILCs, respectively [31,32,96]. ...
... ILCs reside in a variety of tissues and can proliferate and enrich regionally [109,110], which helps the innate immune system to quickly initiate defensive responses and participate in tissue repair and homeostasis [111]. In pathological settings, ILCs can be supplemented from bone marrow or lymphoid organ precursors, in addition to local proliferation [109,112]. ...
... The main effector cells of chronic allograft rejection are recipient-derived macrophages. It has been reported that CX3CR1 + mononuclear phagocytes maintain the proliferation and survival of ILC3s by secreting IL-23 and IL-1β and promote the secretion of IL-22 by ILC3s, thus accelerating fibroblast proliferation and fibrosis [134,[141][142][143]. M1 macrophages have been reported to secrete IL-23 and IL-1β to promote CXCR5 expression by ILC3s, which migrate to the lungs along the CXCR5/CXCL13 axis and promote the formation of pulmonary granuloma by secreting IL-22 and IL-17 [112]. However, the mechanism underlying the interaction between macrophages and ILC3s in the allograft microenvironment has not been reported. ...
Organ fibrosis caused by chronic allograft rejection is a major concern in the field of transplantation. Macrophage-to-myofibroblast transition plays a critical role in chronic allograft fibrosis. Adaptive immune cells (such as B and CD4⁺ T cells) and innate immune cells (such as neutrophils and innate lymphoid cells) participate in the occurrence of recipient-derived macrophages transformed to myofibroblasts by secreting cytokines, which eventually leads to fibrosis of the transplanted organ. This review provides an update on the latest progress in understanding the plasticity of recipient-derived macrophages in chronic allograft rejection. We discuss here the immune mechanisms of allograft fibrosis and review the reaction of immune cells in allograft. The interactions between immune cells and the process of myofibroblast formulation are being considered for the potential therapeutic targets of chronic allograft fibrosis. Therefore, research on this topic seems to provide novel clues for developing strategies for preventing and treating allograft fibrosis.
... As elaborated in this section, these cells promote the recruitment of other immune cells, driving airway inflammation and tissue damage. Following infection, ILC2/3 cells rapidly accumulate in the airways, promoting the recruitment of monocyte-derived macrophages and neutrophils (Ardain et al., 2019). In a murine model, ILC3s accumulate in the airways early in the infection, followed by ILC2 later. ...
... These cells precede the accumulation of monocytes and monocyte-derived macrophages in the airways. Interestingly, mice that lacked ILC3s exhibited a significant reduction in early AMs (Ardain et al., 2019). During M.tb infection, CXCR5 expression on circulating ILC3s is upregulated, and parallel increases in plasma levels of its ligand, CXCL13, have been observed in human studies. ...
... During M.tb infection, CXCR5 expression on circulating ILC3s is upregulated, and parallel increases in plasma levels of its ligand, CXCL13, have been observed in human studies. This implies that ILC3s migrate in response to CXCL13 concentration gradient (Ardain et al., 2019). Moreover, IL-23dependent expansion of ILC3s in mice and the production of the cytokines IL-17 and IL-22 are critical inducers of lung CXCL13, promoting early mobilization of lung ILC3 and macrophages to initiate inflammation in an attempt to control tuberculosis. ...
Pulmonary tuberculosis is increasingly recognized as a risk factor for COPD. Severe lung function impairment has been reported in post-TB patients. Despite increasing evidence to support the association between TB and COPD, only a few studies describe the immunological basis of COPD among TB patients following successful treatment completion. In this review, we draw on well-elaborated Mycobacterium tuberculosis -induced immune mechanisms in the lungs to highlight shared mechanisms for COPD pathogenesis in the setting of tuberculosis disease. We further examine how such mechanisms could be exploited to guide COPD therapeutics.
... We also observed that IL-17A-secreting antigen-specific CD4 + or CD8 + T cell responses after vaccination correlated with immunoprotection in C57BL/6 mice two weeks post-challenge. Evidence suggests that IL-17 secretion, which can be partly attributed to gamma-delta T (γδT) cells and Group 3 innate lymphoid (ILC3) cells, can enhance phagocytic capacity and antigen presentation 51,52 . Following vaccination with an attenuated MTB ΔLprG vaccine, increase of IL-17A levels in serum was associated with a decrease in bacterial burden in the lungs after the MTB challenge 53 . ...
Mycobacterium avium subspecies paratuberculosis (MAP) causes paratuberculosis (PTB), which is a granulomatous enteritis in ruminants that threatens the dairy industry’s healthy development and public health safety worldwide. Because the commercial inactivated vaccines are not completely protective and interfere with bovine tuberculosis diagnostics, we tested four fusion proteins, namely 66NC, 66CN, 90NC, and 90CN, which were constructed with MAP3527, Ag85B, and Hsp70 of MAP in different tandem combinations. Notably, 66NC, which encodes a 66 kDa fusion protein that combines in linear order MAP3527 N40–232 , Ag85B 41–330 , and MAP3527 C231–361, induced a powerful and specific IFN-γ response. Immunization of C57BL/6 mice with the 66NC fusion protein formulated in Montanide ISA 61 VG adjuvant generated robust Th1, Th2, and Th17 type immune responses and strong antibody responses. The 66NC vaccine protected C57BL/6 mice against virulent MAP K-10 infection. This resulted in a reduction of bacterial load and improvement of pathological damage in the liver and intestine, in addition to a reduction of body weight loss; significantly better protection than the reported 74 F vaccine was also induced. Furthermore, vaccine efficacy correlated with the levels of IFN-γ-, TNF-α-, and IL-17A-secreting antigen-specific CD4 ⁺ and CD8 ⁺ T lymphocytes as well as with serum IFN-γ and TNF-α levels after vaccination. These results demonstrate that recombinant protein 66NC is an efficient candidate for further development into a protective vaccine in terms of inducing specific protection against MAP.
... It was found that, in contrast to ILC1s and ILC2s, ILC3 is required for early protection against TB. The expansion of ILC3s and the production of IL-17 and IL-22 are key factors in the formation of granuloma-protective lymphoid follicles (Ardain et al., 2019). By analyzing the clinical data of patients with COVID-19, it was found that the ILCs were negatively correlated with the probability, duration of hospitalization, and severity of infection, which supported the importance of ILCs in disease tolerance (Silverstein et al., 2022). ...
Resistance and tolerance are two important strategies employed by the host immune response to defend against pathogens. Multidrug-resistant bacteria affect the resistance mechanisms involved in pathogen clearance. Disease tolerance, defined as the ability to reduce the negative impact of infection on the host, might be a new research direction for the treatment of infections. The lungs are highly susceptible to infections and thus are important for understanding host tolerance and its precise mechanisms. This review focuses on the factors that induce lung disease tolerance, cell and molecular mechanisms involved in tissue damage control, and the relationship between disease tolerance and sepsis immunoparalysis. Understanding the exact mechanism of lung disease tolerance could allow better assessment of the immune status of patients and provide new ideas for the treatment of infections.
... These SCFAs not only have high antimicrobial activity but also promote the proliferation of type 3 innate lymphoid cells (ILC3s) (Correâ-Oliveira et al., 2016;Chun et al., 2019). ILC3s are associated with the increase in alveolar macrophages, which can protect the host from MTB infection (Ardain et al., 2019). ...
Objective
To determine the effects of second-line anti-tuberculosis (TB) drugs on the composition and functions of intestinal microbiota in patients with rifampicin-resistant TB (RR-TB).
Methods
In this cross-sectional study, stool samples and relevant clinical information were collected from patients with RR-TB admitted to the Drug-resistant Specialty Department at Hunan Chest Hospital (Hunan Institute For Tuberculosis Control). The composition and functions of intestinal microbiota were analyzed using metagenomic sequencing and bioinformatics methods.
Results
Altered structural composition of the intestinal microbiota was found when patients from the control, intensive phase treatment, and continuation phase treatment groups were compared (P<0.05). Second-line anti-TB treatment resulted in a decrease in the relative abundance of species, such as Prevotella copri , compared with control treatment. However, the relative abundance of Escherichia coli , Salmonella enterica , and 11 other conditionally pathogenic species increased significantly in the intensive phase treatment group. Based on differential functional analysis, some metabolism-related functions, such as the biosynthesises of phenylalanine, tyrosine, and tryptophan, were significantly inhibited during second-line anti-TB drug treatment, while other functions, such as phenylalanine metabolism, were significantly promoted during the intensive phase of treatment.
Conclusion
Second-line anti-TB drug treatment caused changes in the structural composition of the intestinal microbiota in patients with RR-TB. In particular, this treatment induced a significant increase in the relative abundance of 11 conditionally pathogenic species, including Escherichia coli. Functional analysis revealed significantly decreased biosynthesises of phenylalanine, tyrosine, and tryptophan and significantly increased phenylalanine metabolism.
... Recent studies demonstrated that Mycobacterium tuberculosis (Mtb) infection induces ILCs accumulation in the lungs [44,154]. Furthermore, Mtb can induce IL-18R + ILCs in the lungs [44]. ...
... Furthermore, Mtb can induce IL-18R + ILCs in the lungs [44]. It was also found that Mtb infection changes ILC composition, leading to accumulation of protective IFNγ-producing ILC1s and IL-17 producing ILC3s [154] in parallel with reduction of ILC2s [44]. Lung IL-18R + ILCs are mainly ILC2-like cells, characterized by GATA3 and ST2 (IL-33 receptor) expression [44]. ...
... Although IFNγ is important for protection against Mtb, a recent study suggests that IL-22 and IL-17 producing ILC3s can also contribute to protective immune response, potentially via maintenance of inducible bronchus-associated lymphoid tissue (iBALT) [154]. Therefore, it is tempting to speculate that Mtb can also promote ILC3→ILC2 plasticity ( Figure 5). ...
Mucosal tissue homeostasis is a dynamic process that involves multiple mechanisms including regulation of innate lymphoid cells (ILCs). ILCs are mostly tissue-resident cells which are critical for tissue homeostasis and immune response against pathogens. ILCs can sense environmental changes and rapidly respond by producing effector cytokines to limit pathogen spread and initiate tissue recovery. However, dysregulation of ILCs can also lead to immunopathology. Accumulating evidence suggests that ILCs are dynamic population that can change their phenotype and functions under rapidly changing tissue microenvironment. However, the significance of ILC plasticity in response to pathogens remains poorly understood. Therefore, in this review, we discuss recent advances in understanding the mechanisms regulating ILC plasticity in response to intestinal, respiratory and genital tract pathogens. Key transcription factors and lineage-guiding cytokines regulate this plasticity. Additionally, we discuss the emerging data on the role of tissue microenvironment, gut microbiota, and hypoxia in ILC plasticity in response to mucosal pathogens. The identification of new pathways and molecular mechanisms that control functions and plasticity of ILCs could uncover more specific and effective therapeutic targets for infectious and autoimmune diseases where ILCs become dysregulated.
... We also observed that IL-17A-secreting antigen-speci c CD4 + or CD8 + T cell responses after vaccination correlated with protection in C57BL/6 mice two weeks post challenge. Evidence suggests that IL-17 secretion, which can be attributed to gamma-delta T (γδT) cells and Group 3 innate lymphoid (ILC3) cells, can enhance phagocytic capacity and antigen presentation 50,51 . Following vaccination with an attenuated MTB ΔLprG vaccine, an increase in serum IL-17A levels was observed, which was associated with a decrease in bacterial burden in the lungs after the MTB challenge 52 . ...
Mycobacterium avium subsp. paratuberculosis (MAP) causes paratuberculosis (PTB), which is a granulomatous enteritis in ruminants that threatens the dairy industry’s healthy development and public health safety worldwide. Because the commercial inactivated vaccines are not completely protective and interfere with bovine tuberculosis diagnostics, we identified a polyprotein (66NC) from four fusion proteins, namely 66NC, 66CN, 90NC, and 90CN, which were constructed with MAP3257, Ag85B, and Hsp70 of MAP in different tandem combinations. Notably, 66NC, which encodes a 66 kDa fusion protein that combines in linear order MAP3527 N40–232 , Ag85B 41–330 , and MAP3527 C231–361, induced a powerful and specific IFN- γ response. Immunization of C57BL/6 mice with the 66NC fusion protein formulated in MONTANIDE ISA 61 VG adjuvant generated robust Th1, Th2, and Th17 type immune responses and strong antibody responses. The 66NC vaccine protected C57BL/6 mice against virulent MAP K-10 infection. This resulted in a reduction of bacterial load and improvement of pathological damage in the liver and intestine, in addition to a reduction of body weight loss; significantly better protection than the reported 74F vaccine was also induced. Furthermore, vaccine efficacy correlated with the levels of IFN-γ-, TNF-α-, and IL-17A-secreting antigen-specific CD4 ⁺ and CD8 ⁺ T lymphocytes as well as with serum IFN-γ and TNF-α levels after vaccination. These results demonstrate that recombinant protein 66NC is an efficient candidate for further development into a protective vaccine in terms of inducing specific protection against MAP.
