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Triggering receptor expressed on myeloid cells 1 (TREM-1) is a receptor mainly expressed on myeloid cells, and it plays an important role in modulating immune response against infectious agents. The function of TREM-1 on nonmyeloid cells such as Vϐ2 T cells has not been characterized and their role in pulmonary tuberculosis (TB) remains unclear. To assess the expression of TREM-1 on blood Vϐ2 T cells from pulmonary TB patients and investigate its mechanism of induction, we exploited flow cytometry analysis to study the expression of TREM-1 on Vϐ2 T cells from active pulmonary TB patients and control subjects. In this study we demonstrate that TREM-1 (TREM-1+) is highly expressed on Vd2 T cells of patients with active pulmonary TB. Unlike TREM-12-expressing Vϐ2 T cells, TREM-1+-producing Vϐ2 T cells display APC-like phenotypes. Surprisingly, TREM-1+ signaling promotes the Ag-presenting capability of Vϐ2 T cells to induce the CD4+ T cell response. TREM-1+Vϐ2 T cells induced the proliferation and differentiation of naive CD4+ T cells, as well as the elimination of intracellular mycobacteria. We identified TREM-1+ (but not TREM-12) as an Ag-presentation amplifier on human blood Vϐ2 T cells, and data shed new light on the regulation of V&ϐ#976;2 T cells in the phase of innate and adaptive immune responses against Mycobacterium tuberculosis infection. Targeting TREM-1+V2ϐ T cells may be a promising approach for TB therapy. [ABSTRACT FROM AUTHOR]

Triggering receptor expressed on myeloid cells 1 (TREM-1) is a receptor mainly expressed on myeloid cells, and it plays an important role in modulating immune response against infectious agents. The function of TREM-1 on nonmyeloid cells such as Vδ2 T cells has not been characterized, and their role in pulmonary tuberculosis (TB) remains unclear. To assess the expression of TREM-1 on blood Vδ2 T cells from pulmonary TB patients and investigate its mechanism of induction, we exploited flow cytometry analysis to study the expression of TREM-1 on Vδ2 T cells from active pulmonary TB patients and control subjects. In this study we demonstrate that TREM-1 (TREM-1 + ) is highly expressed on Vδ2 T cells of patients with active pulmonary TB. Unlike TREM-1 - -expressing Vδ2 T cells, TREM-1 + -producing Vδ2 T cells display APC-like phenotypes. Surprisingly, TREM-1 + signaling promotes the Ag-presenting capability of Vδ2 T cells to induce the CD4 + T cell response. TREM-1 + Vδ2 T cells induced the proliferation and differentiation of naive CD4 + T cells, as well as the elimination of intracellular mycobacteria. We identified TREM-1 + (but not TREM-1 - ) as an Ag-presentation amplifier on human blood Vδ2 T cells, and data shed new light on the regulation of Vδ2 T cells in the phase of innate and adaptive immune responses against Mycobacterium tuberculosis infection. Targeting TREM-1 + Vδ2 T cells may be a promising approach for TB therapy., (Copyright © 2018 by The American Association of Immunologists, Inc.)

The contribution of lymphotoxin (LT)α in the host immune response to virulent Mycobacterium tuberculosis and Mycobacterium bovis bacillus Calmette-Guérin infections was investigated. Despite their ability to induce Th1 cytokine, IFN-γ, and IL-12 pulmonary response, "conventional" LTα(-/-) mice succumb rapidly to virulent M. tuberculosis aerosol infection, with uncontrolled bacilli growth, defective granuloma formation, necrosis, and reduced pulmonary inducible NO synthase expression, similar to TNF(-/-) mice. Contributions from developmental lymphoid abnormalities in LTα(-/-) mice were excluded because hematopoietic reconstitution with conventional LTα(-/-) bone marrow conferred enhanced susceptibility to wild-type mice, comparable to conventional LTα(-/-) control mice. However, conventional LTα(-/-) mice produced reduced levels of TNF after M. bovis bacillus Calmette-Guérin infection, and their lack of control of mycobacterial infection could be due to a defective contribution of either LTα or TNF, or both, to the host immune response. To address this point, the response of "neo-free" LTα(-/-) mice with unperturbed intrinsic TNF expression to M. tuberculosis infection was investigated in a direct comparative study with conventional LTα(-/-) mice. Strikingly, although conventional LTα(-/-) mice were highly sensitive, similar to TNF(-/-) mice, neo-free LTα(-/-) mice controlled acute M. tuberculosis infection essentially as wild-type mice. Pulmonary bacterial burden and inflammation was, however, slightly increased in neo-free LTα(-/-) mice 4-5 mo postinfection, but importantly, they did not succumb to infection. Our findings revise the notion that LTα might have a critical role in host defense to acute mycobacterial infection, independent of TNF, but suggest a contribution of LTα in the control of chronic M. tuberculosis infection.

Lung emphysema and fibrosis are severe complications of chronic obstructive pulmonary disease, and uncontrolled protease activation may be involved in the pathogenesis. Using experimental elastase-induced acute inflammation, we demonstrate here that inflammation and development of emphysema is IL-1R1 and Toll/IL-1R signal transduction adaptor MyD88 dependent; however, TLR recognition is dispensable in this model. Elastase induces IL-1beta, TNF-alpha, keratinocyte-derived chemokine, and IL-6 secretion and neutrophil recruitment in the lung, which is drastically reduced in the absence of IL-1R1 or MyD88. Further, tissue destruction with emphysema and fibrosis is attenuated in the lungs of IL-1R1- and MyD88-deficient mice. Specific blockade of IL-1 by IL-1R antagonist diminishes acute inflammation and emphysema. Finally, IL-1beta production and inflammation are reduced in mice deficient for the NALP3 inflammasome component apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), and we identified uric acid, which is produced upon elastase-induced lung injury, as an activator of the NALP3/ASC inflammasome. In conclusion, elastase-mediated lung pathology depends on inflammasome activation with IL-1beta production. IL-1beta therefore represents a critical mediator and a possible therapeutic target of lung inflammation leading to emphysema.

MyD88, the common adapter involved in TLR, IL-1, and IL-18 receptor signaling, is essential for the control of acute Mycobacterium tuberculosis (MTB) infection. Although TLR2, TLR4, and TLR9 have been implicated in the response to mycobacteria, gene disruption for these TLRs impairs only the long-term control of MTB infection. Here, we addressed the respective role of IL-1 and IL-18 receptor pathways in the MyD88-dependent control of acute MTB infection. Mice deficient for IL-1R1, IL-18R, or Toll-IL-1R domain-containing adaptor protein (TIRAP) were compared with MyD88-deficient mice in an acute model of aerogenic MTB infection. Although primary MyD88-deficient macrophages and dendritic cells were defective in cytokine production in response to mycobacterial stimulation, IL-1R1-deficient macrophages exhibited only a reduced IL-12p40 secretion with unaffected TNF, IL-6, and NO production and up-regulation of costimulatory molecules CD40 and CD86. Aerogenic MTB infection of IL-1R1-deficient mice was lethal within 4 wk with 2-log higher bacterial load in the lung and necrotic pneumonia but efficient pulmonary CD4 and CD8 T cell responses, as seen in MyD88-deficient mice. Mice deficient for IL-18R or TIRAP controlled acute MTB infection. These data demonstrate that absence of IL-1R signal leads to a dramatic defect of early control of MTB infection similar to that seen in the absence of MyD88, whereas IL-18R and TIRAP are dispensable, and that IL-1, together with IL-1-induced innate response, might account for most of MyD88-dependent host response to control acute MTB infection.

Neutralization of the proinflammatory cytokine TNF-alpha by mAbs or soluble receptors represents an effective treatment for chronic inflammatory disorders such as rheumatoid arthritis, psoriasis, or Crohn's disease. In this study, we describe a novel active immunization approach against TNF-alpha, which results in the induction of high titers of therapeutically active autoantibodies. Immunization of mice with virus-like particles of the bacteriophage Qbeta covalently linked to either the entire soluble TNF-alpha protein (Qbeta-C-TNF(1-156)) or a 20-aa peptide derived from its N terminus (Qbeta-C-TNF(4-23)) yielded specific Abs, which protected from clinical signs of inflammation in a murine model of rheumatoid arthritis. Whereas mice immunized with Qbeta-C-TNF(1-156) showed increased susceptibility to Listeria monocytogenes infection and enhanced reactivation of latent Mycobacterium tuberculosis, mice immunized with Qbeta-C-TNF(4-23) were not immunocompromised with respect to infection with these pathogens. This difference was attributed to recognition of both transmembrane and soluble TNF-alpha by Abs elicited by Qbeta-C-TNF(1-156), and a selective recognition of only soluble TNF-alpha by Abs raised by Qbeta-C-TNF(4-23). Thus, by specifically targeting soluble TNF-alpha, Qbeta-C-TNF(4-23) immunization has the potential to become an effective and safe therapy against inflammatory disorders, which might overcome the risk of opportunistic infections associated with the currently available TNF-alpha antagonists.

Because histamine receptor type I blockade attenuates allergic asthma, we asked whether complete neutralization of histamine by an arthropod-derived, high affinity histamine-binding protein (EV131) would prevent allergic asthma. Intranasal administration of EV131 given before Ag challenge in immunized mice prevented airway hyperreactivity by 70%, and abrogated peribronchial inflammation, pulmonary eosinophilia, mucus hypersecretion, and IL-4 and IL-5 secretion. Saturation with histamine abrogated the inhibitory effect of EV131 on bronchial hyperreactivity. The inhibitory effect of EV131 on bronchial hyperreactivity was comparable to that of glucocorticosteroids. These results demonstrate that histamine is a critical mediator of allergic asthma. Therefore, complete neutralization of histamine, rather than specific histamine receptor blockade, may have a profound effect on allergic asthma.