Role of Th1/Th17 Balance Regulated by T-bet in a Mouse Model of <i>Mycobacterium avium</i> Complex Disease

Matsuyama, Masashi; Ishii, Yukio; Yageta, Yuichi; Ohtsuka, Shigeo; Ano, Satoshi; Matsuno, Yosuke; Morishima, Yuko; Yoh, Keigyou; Takahashi, Satoru; Ogawa, Kenji; Hogaboam, Cory M.; Hizawa, Nobuyuki

doi:10.4049/jimmunol.1302258

Cited by 32 publications

(31 citation statements)

References 49 publications

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“…A number of studies have demonstrated that MAC disease is associated with the host immune system [ 4 – 7 ]. A granuloma is a characteristic pathophysiological feature induced by mycobacterial infections, and is an important element of the host defense system.…”

Section: Introductionmentioning

confidence: 99%

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Persimmon-derived tannin has bacteriostatic and anti-inflammatory activity in a murine model of Mycobacterium avium complex (MAC) disease

et al. 2017

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Nontuberculous mycobacteria (NTM), including Mycobacterium avium complex (MAC), cause opportunistic chronic pulmonary infections. Notably, MAC susceptibility is regulated by various factors, including the host immune system. Persimmon (Ebenaceae Diospyros kaki Thunb.) tannin is a condensed tannin composed of a polymer of catechin groups. It is well known that condensed tannins have high antioxidant activity and bacteriostatic properties. However, it is hypothesized that condensed tannins might need to be digested and/or fermented into smaller molecules in vivo prior to being absorbed into the body to perform beneficial functions. In this study, we evaluated the effects of soluble persimmon-derived tannins on opportunistic MAC disease. Soluble tannins were hydrolyzed and evaluated by the oxygen radical absorbance capacity (ORAC) method. The ORAC value of soluble tannin hydrolysate was approximately five times greater than that of soluble tannin powder. In addition, soluble tannin hydrolysate exhibited high bacteriostatic activity against MAC in vitro. Furthermore, in an in vivo study, MAC infected mice fed a soluble tannin-containing diet showed significantly higher anti-bacterial activity against MAC and less pulmonary granuloma formation compared with those fed a control diet. Tumor necrosis factor α and inducible nitric oxide synthase levels were significantly lower in lungs of the soluble tannin diet group compared with the control diet group. Moreover, proinflammatory cytokines induced by MAC stimulation of bone marrow-derived macrophages were significantly decreased by addition of soluble tannin hydrolysate. These data suggest that soluble tannin from persimmons might attenuate the pathogenesis of pulmonary NTM infection.

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Section: Introductionmentioning

confidence: 99%

“…Th1 cells also play a central role in protection against intracellular pathogens and induce activation of macrophages. Thus, they are deeply involved in inflammation and granuloma formation, which play critical roles in protection against MAC [ 4 ].…”

Section: Introductionmentioning

confidence: 99%

Persimmon-derived tannin has bacteriostatic and anti-inflammatory activity in a murine model of Mycobacterium avium complex (MAC) disease

et al. 2017

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“…The transcription factor T-box expressed in T cells (T-bet) is known as the critical regulator of Th1 differentiation and Th1 cytokine production [ 8 ]. We recently demonstrated that T-bet-overexpressing mice were resistant to pulmonary MAC infection and their cytokine expression was shifted toward Th1 phenotype [ 9 ]. However, T-bet-deficient mice were susceptible to MAC and had a higher expression of Th17 cytokines, such as IL-6 and IL-17.…”

Section: Introductionmentioning

confidence: 99%

Overexpression of RORγt Enhances Pulmonary Inflammation after Infection with Mycobacterium Avium

et al. 2016

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Mycobacterium avium complex (MAC) is the most common cause of nontuberculous mycobacterial disease in humans. The role of Th17 immunity in the pathogenesis of intracellular bacteria, such as MAC, is not currently understood. Transcription factor RAR-related orphan receptor gamma t (RORγt) is known as the master regulator for Th17 cell development. Here, we investigated the role of RORγt in host responses against MAC infection. Wild-type (WT) mice and RORγt-overexpressing mice were infected with MAC via intratracheal inoculation. Systemic MAC growth was not different between WT mice and RORγt-overexpressing mice. However, neutrophilic pulmonary inflammation following MAC infection was enhanced in RORγt-overexpressing mice compared with that in WT mice. The cytokine expression shifted toward a Th17 phenotype in the lungs of RORγt-overexpressing mice following MAC infection; the levels of IL-6 and IL-17 were significantly higher in the lung of these mice than in WT mice. In addition to the increase in IL-17 single-positive T cells, T cells producing both IL-17 and interferon-γ were elevated in the lung of RORγt-overexpressing mice following MAC infection. These findings suggest that RORγt overexpression-mediated Th17 bias contributes to local inflammation rather than systemic responses, by regulating neutrophil recruitment into the sites of infection during MAC infection.

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“…Key observations made in T-bet-deficient mice were validated in this human patient with T-bet deficiency: 1) the development of TH1 cells and their production of effector cytokines, including IFN-g in particular, requires T-bet (Szabo et al, 2000(Szabo et al, , 2002; 2) the development of NK and iNKT cells is dependent on T-bet (Townsend et al, 2004) (Table S8); 3) the regulation of T-bet-dependent targets, including CXCR3, TNF and IFNG, involves both direct transactivation and epigenetic modulation (Miller and Weinmann, 2010). Accordingly, T-betdeficient mice are highly vulnerable to mycobacteria, including Mycobacterium tuberculosis and Mycobacterium avium (Matsuyama et al, 2014;Sullivan et al, 2005), like mice deficient for other genes that govern IFN-g immunity (Casanova, 1999). By contrast, despite the requirement of Tbet for immunity against a broad spectrum of pathogens following experimental inoculation in mice, the only apparent infectious phenotype of the T-bet-deficient patient is MSMD (Table S9).…”

Section: Discussionmentioning

confidence: 99%

Human T-bet governs innate and innate-like adaptive IFN-γ immunity against mycobacteria

Yang

Mele²,

Worley

et al. 2020

Preprint

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SummaryInborn errors of human IFN-γ immunity underlie mycobacterial disease. We report a patient with mycobacterial disease due to an inherited deficiency of the transcription factor T-bet. This deficiency abolishes the expression of T-bet target genes, including IFNG, by altering chromatin accessibility and DNA methylation in CD4+ T cells. The patient has profoundly diminished counts of mycobacterial-reactive circulating NK, invariant NKT (iNKT), mucosal-associated invariant T (MAIT), and Vδ2+ γδ T lymphocytes, and of non-mycobacterial-reactive classic TH1 lymphocytes, the remainders of which also produce abnormally low amounts of IFN-γ. Other IFN-γ-producing lymphocyte subsets however develop normally, but with low levels of IFN-γ production, with exception of Vδ2− γδ T lymphocytes, which produce normal amounts of IFN-γ in response to non-mycobacterial stimulation, and non-classic TH1 (TH1*) lymphocytes, which produce IFN-γ normally in response to mycobacterial antigens. Human T-bet deficiency thus underlies mycobacterial disease by preventing the development of, and IFN-γ production by, innate (NK) and innate-like adaptive lymphocytes (iNKT, MAIT, and Vδ2+ γδ T cells), with mycobacterial-specific, IFN-γ-producing, purely adaptive αβ TH1* cells unable to compensate for this deficit.

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Role of Th1/Th17 Balance Regulated by T-bet in a Mouse Model of Mycobacterium avium Complex Disease

Cited by 32 publications

References 49 publications

Persimmon-derived tannin has bacteriostatic and anti-inflammatory activity in a murine model of Mycobacterium avium complex (MAC) disease

Persimmon-derived tannin has bacteriostatic and anti-inflammatory activity in a murine model of Mycobacterium avium complex (MAC) disease

Overexpression of RORγt Enhances Pulmonary Inflammation after Infection with Mycobacterium Avium

Human T-bet governs innate and innate-like adaptive IFN-γ immunity against mycobacteria

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