CD40 ligand and interferon‐γ induce an antimicrobial response against <i><scp>M</scp>ycobacterium tuberculosis</i> in human monocytes

Klug-Micu, Georgiana M; Stenger, Steffen; Sommer, Andrea; Liu, Philip T.; Krutzik, Stephan R.; Modlin, Robert L.; Fabri, Mario

doi:10.1111/imm.12062

Cited by 75 publications

(65 citation statements)

References 38 publications

(82 reference statements)

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“…This suggests that interactions between activated T cells and macrophages might induce mechanisms that allow efficient conversion of 25(OH)D 3 to 1,25(OH) 2 D 3 in vivo despite the presence of DBP. This is in good accordance with previous studies which found that treatment of macrophages with IFN-γ or soluble CD40L increases their expression of CYP27B1 and their capacity to convert 25(OH)D 3 to 1,25(OH) 2 D 3 [59-61]. Thus, whether vitamin D actually affects a given T cell response in vivo probably relies on a mixture of factors in addition to the concentration of 25(OH)D 3 such as the isotype, local concentration and degradation rate of DBP and the expression levels of CYP27B1, the VDR and the 1,25(OH) 2 D 3 -24-hydroxylase CYP24A1 of the cells locally involved in the immune response.…”

Section: Discussionsupporting

confidence: 93%

Vitamin D-binding protein controls T cell responses to vitamin D

et al. 2014

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BackgroundIn vitro studies have shown that the active form of vitamin D3, 1α,25-dihydroxyvitamin D3 (1,25(OH)2D3), can regulate differentiation of CD4+ T cells by inhibiting Th1 and Th17 cell differentiation and promoting Th2 and Treg cell differentiation. However, the serum concentration of 1,25(OH)2D3 is far below the effective concentration of 1,25(OH)2D3 found in in vitro studies, and it has been suggested that 1,25(OH)2D3 must be produced locally from the inactive precursor 25-hydroxyvitamin D3 (25(OH)D3) to affect ongoing immune responses in vivo. Although it has been reported that activated T cells express the 25(OH)D-1α-hydroxylase CYP27B1 that converts 25(OH)D3 to 1,25(OH)2D3, it is still controversial whether activated T cells have the capacity to produce sufficient amounts of 1,25(OH)2D3 to affect vitamin D-responsive genes. Furthermore, it is not known how the vitamin D-binding protein (DBP) found in high concentrations in serum affects T cell responses to 25(OH)D3.ResultsWe found that activated T cells express CYP27B1 and have the capacity to produce sufficient 1,25(OH)2D3 to affect vitamin D-responsive genes when cultured with physiological concentrations of 25(OH)D3 in serum-free medium. However, if the medium was supplemented with serum or purified DBP, DBP strictly inhibited the production of 1,25(OH)2D3 and 25(OH)D3-induced T cell responses. In contrast, DBP did not inhibit the effect of exogenous 1,25(OH)2D3. Actin, arachidonic acid and albumin did not affect the sequestration of 25(OH)D3 by DBP, whereas carbonylation of DBP did.ConclusionsActivated T cells express CYP27B1 and can convert 25(OH)D3 to 1,25(OH)2D3 in sufficiently high concentrations to affect vitamin D-responsive genes when cultured in serum-free medium. However, DBP sequesters 25(OH)D3 and inhibits the production of 1,25(OH)2D3 in T cells. To fully exploit the immune-regulatory potential of vitamin D, future studies of the mechanisms that enable the immune system to exploit 25(OH)D3 and convert it to 1,25(OH)2D3in vivo are required.Electronic supplementary materialThe online version of this article (doi:10.1186/s12865-014-0035-2) contains supplementary material, which is available to authorized users.

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Section: Discussionsupporting

confidence: 93%

Vitamin D-binding protein controls T cell responses to vitamin D

et al. 2014

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“…This leads us to speculate that VDR agonists could be used therapeutically to increase cathelicidin production in TAMs and enhance their cytotoxic activity in vivo. It is worth noting that the expression of cathelicidin is also up-regulated by mycobacterial antigens, interferon-g (12), and CD40 ligand (40) in human macrophages. Recent studies also indicate that macrophage tumoricidal activity could be therapeutically enhanced upon administration of live mycobacterium Bacille Calmette-Guérin (41), muramyl tripeptide (42), or CD40 agonistic antibodies (2).…”

Section: Discussionmentioning

confidence: 99%

Vitamin D–dependent induction of cathelicidin in human macrophages results in cytotoxicity against high-grade B cell lymphoma

et al. 2015

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Infiltration by macrophages represents a characteristic morphological hallmark in high-grade lymphatic malignancies such as Burkitt's lymphoma (BL). Although macrophages can, in principle, target neoplastic cells and mediate antibody-dependent cellular cytotoxicity (ADCC), tumor-associated macrophages (TAMs) regularly fail to exert direct cytotoxic functions. The underlying mechanisms responsible for this observation remain unclear. We demonstrate that inflammatory M1 macrophages kill proliferating high-grade B cell lymphoma cells by releasing the antimicrobial peptide cathelicidin in a vitamin D-dependent fashion. We show that cathelicidin directly induces cell death by targeting mitochondria of BL cells. In contrast, anti-inflammatory M2 macrophages and M2-like TAMs in BL exhibit an altered vitamin D metabolism, resulting in a reduced production of cathelicidin and consequently in inability to lyse BL cells. However, treatment of M2 macrophages with the bioactive form of vitamin D, 1,25D3, or a vitamin D receptor agonist effectively induces cathelicidin production and triggers tumoricidal activity against BL cells. Furthermore, rituximab-mediated cytotoxicity of vitamin D-treated M2 macrophages is cathelicidin-dependent. Finally, vitamin D treatment of 25-hydroxyvitamin D (25D)-deficient volunteers in vivo or primary TAMs in vitro improves rituximab-mediated ADCC against B cell lymphoma cells. These data indicate that activation of the vitamin D signaling pathway activates antitumor activity of TAMs and improves the efficacy of ADCC.

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“…Today we recognize that autophagy is widely integrated with immunity starting from cell-autonomous defense against invading bacteria and viruses to regulation of innate and adaptive immunity in general ). The initial observations uncovering the role of autophagy against M. tuberculosis (Gutierrez et al 2004;Singh et al 2006) have been followed by a gradual increase in studies supporting and extending these early findings (Alonso et al 2007;Harris et al 2007;Xu et al 2007;Biswas et al 2008;Jagannath et al 2009;Yuk et al 2009;Ghadimi et al 2010;Kumar et al 2010;Ponpuak et al 2010;Shin et al 2010b;Singh et al 2010;Fabri et al 2011a,b;Campbell and Spector 2012;Juarez et al 2012;Petruccioli et al 2012;Watson et al 2012;Zullo and Lee 2012;Anandaiah et al 2013;Klug-Micu et al 2013;Manzanillo et al 2013). In this article we briefly cover autophagy as a pathway and its broad roles in immunity and summarize what has been learned about autophagy in tuberculosis thus far.…”

mentioning

confidence: 93%

Autophagy in Tuberculosis

Deretic

2014

Cold Spring Harbor Perspectives in Medicine

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CD40 ligand and interferon‐γ induce an antimicrobial response against Mycobacterium tuberculosis in human monocytes

Cited by 75 publications

References 38 publications

Vitamin D-binding protein controls T cell responses to vitamin D

Vitamin D-binding protein controls T cell responses to vitamin D

Vitamin D–dependent induction of cathelicidin in human macrophages results in cytotoxicity against high-grade B cell lymphoma

Autophagy in Tuberculosis

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