<i>Mycobacterium bovis</i> BCG Attenuates Surface Expression of Mature Class II Molecules through IL-10-Dependent Inhibition of Cathepsin S

Sendide, Khalid; Deghmane, Ala‐Eddine; Pechkovsky, Dmitri V.; Av‐Gay, Yossef; Talal, Amina; Hmama, Zakaria

doi:10.4049/jimmunol.175.8.5324

Cited by 85 publications

(84 citation statements)

References 67 publications

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“…Resting BMMs express very low levels of MHC II on their surface, therefore, the effect of lactoferrin was also examined on IFN-γ activated BCG-infected BMMs. BCG infection of IFN-γ activated BMMs dramatically decreased MHC II + BMMs, a trend that has been previously reported [60][61][62]. The presence of lactoferrin was able to reverse a significant percentage of the BCG induced down regulation of MHC II surface expression, again suggesting that lactoferrin enables activated macrophages to retain their ability to present antigen to T-cells.…”

Section: Discussionsupporting

confidence: 79%

Influence of bovine lactoferrin on expression of presentation molecules on BCG-infected bone marrow derived macrophages

Hwang¹,

Kruzel

Actor³

2009

Biochimie

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The current vaccine for tuberculosis (TB), caused by Mycobacterium tuberculosis (MTB), is an attenuated strain of Mycobacterium bovis bacillus Calmette-Guerin (BCG). BCG has proven to be effective in children, however, efficacy wanes in adulthood. Lactoferrin, a natural protein with immunomodulatory properties, is a potential adjuvant candidate to enhance efficacy of BCG. These studies define bovine lactoferrin as an enhancer of the BCG vaccine, functioning in part by modulating macrophage ability to present antigen and stimulate T-cells. BCG-infected bone marrow derived macrophages (BMMs) cultured with bovine lactoferrin increased the number of MHC II + expressing cells. Addition of IFN-γ and lactoferrin to BCG-infected BMMs enhanced MHC II expressiona dna increased the ratio of CD86/CD80. Lactoferrin treated BCG-infected BMMs were able to stimulate an increase in IFN-γ production from presensitized CD3 + splenocytes. Together, these results demonstrate that bovine lactoferrin is capable of modulating BCG-infected macrophages to enhance T-cell stimulation through increased surface expression of antigen presentation and costimulatory molecules, which potentially explains the observed in vivo bovine lactoferrin enhancement of BCG vaccine efficacy to protect against virulent MTB infection.

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Section: Discussionsupporting

confidence: 79%

Influence of bovine lactoferrin on expression of presentation molecules on BCG-infected bone marrow derived macrophages

Hwang¹,

Kruzel

Actor³

2009

Biochimie

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“…4B). A considerable body of evidence indicates that IL-10 diminishes macrophage microbicidal capacity (14)(15)(16)(17). In summary, therefore, infection with CH and CAS2 were associated with a pattern of cytokine secretion that would result in phagocyte deactivation favoring the intracellular survival of bacilli.…”

Section: Resultsmentioning

confidence: 99%

A deletion defining a common Asian lineage ofMycobacterium tuberculosisassociates with immune subversion

Newton

Smith

Wilkinson

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

102

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Six major lineages of Mycobacterium tuberculosis appear preferentially transmitted amongst distinct ethnic groups. We identified a deletion affecting Rv1519 in CH, a strain isolated from a large outbreak in Leicester U.K., that coincidentally defines the East African-Indian lineage matching a major ethnic group in this city. In broth media, CH grew less rapidly and was less acidic and H 2 O 2 -tolerant than reference sequenced strains (CDC1551 and H37Rv). Nevertheless, CH was not impaired in its ability to grow in human monocyte-derived macrophages. When compared with CDC1551 and H37Rv, CH induced less protective IL-12p40 and more antiinflammatory IL-10 and IL-6 gene transcription and secretion from monocyte-derived macrophages. It thus appears that CH compensates microbiological attenuation by skewing the innate response toward phagocyte deactivation. Complementation of Rv1519 , but none of nine additional genes absent from CH compared with the type strain, H37Rv, reversed the capacity of CH to elicit antiinflammatory IL-10 production by macrophages. The Rv1519 polymorphism in M. tuberculosis confers an immune subverting phenotype that contributes to the persistence and outbreak potential of this lineage.

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“…Other pro-and anti-inflammatory cytokines such as IL-6 and IL-10 also modulate protease activity upwards or downwards, respectively, at least in part by altering endosomal pH [42,43]. In another study, IL-10, produced by BCG infected macrophages, reduced cathepsin S expression levels, thereby overriding the ability of IFN-g to enhance class II MHC levels and promote T-cell recognition of infected cells [44]. However, another study found that IL-10 (and IL-6) enhanced the activity of various cathepsins, including cathepsin S and that IL-6 diminished DM levels [45].…”

Section: Reciprocal Relationships Between Cytokines and Lysosomal Catmentioning

confidence: 98%

Diverse regulatory roles for lysosomal proteases in the immune response

et al. 2009

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The innate and adaptive immune system utilise endocytic protease activity to promote functional immune responses. Cysteine and aspartic proteases (cathepsins) constitute a subset of endocytic proteases, the immune function of which has been described extensively. Although historically these studies have focused on their role in processes such as antigen presentation and zymogen processing within the endocytic compartment, recent discoveries have demonstrated a critical role for these proteases in other intracellular compartments, and within the extracellular milieu. It has also become clear that their pattern of expression and substrate specificities are more diverse than was first envisaged. Here, we discuss recent advances addressing the role of lysosomal proteases in various aspects of the immune response. We pay attention to reports demonstrating cathepsin activity outside of its canonical endosome/lysosome microenvironment.Key words: Cathepsins . Endosomes . Immune regulation . Lysosomes IntroductionThe endosome/lysosome compartments, together with the cytosolic proteasomes, are the two major protein degradation systems in cells. Both have emerged as having many important regulatory functions in addition to their role in protein breakdown for amino acid recycling. For example, limited proteolysis within the endocytic pathway can induce activating conformational changes [1,2], release functional proteins from chaperones [3], and cleave soluble bioactive molecules from membrane-anchored precursors [4]. The concept of ''regulation through limited destruction'' is evident in many processes in innate and adaptive immunity. Endosome/lysosome-located proteases play key roles in antigen processing and presentation, cytokine regulation, NKT cell development, activation of serine protease zymogens in regulated secretory granules, integrin activation, induction of apoptosis and TLR signalling. Given that these processes may also be associated with undesirable immune responses and inflammation, the proteases involved may be considered as attractive drug targets. EnzymesEndosomes and lysosomes harbour mainly cysteine and aspartic acid proteases so-named because their active site utilises either a cysteine thiol or an aspartic acid as a key part of the catalytic site. Some endosome/lysosome located serine proteases such as cathepsin G, granzymes and thymus specific serine protease (TSSP) have important roles in the immune system; however, we focus primarily here on the cysteine and aspartic proteases. Most of the lysosomal cysteine proteases are related to papain and belong to the so-called C1 family. These include cathepsins L, S, C, F, H, B, X, K, V and W. Cathepsins D and E are also found in lysosomes but are aspartic acid proteases related to pepsin. An additional cysteine protease is found in lysosomes, which is more closely related to the caspases. This is asparaginyl endopeptidase (AEP) or legumain, a member of the C13 family. Some of these enzymes are endopeptidases (cathepsins S, L, K, F, V, D, E and AEP), where...

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Mycobacterium bovis BCG Attenuates Surface Expression of Mature Class II Molecules through IL-10-Dependent Inhibition of Cathepsin S

Cited by 85 publications

References 67 publications

Influence of bovine lactoferrin on expression of presentation molecules on BCG-infected bone marrow derived macrophages

Influence of bovine lactoferrin on expression of presentation molecules on BCG-infected bone marrow derived macrophages

A deletion defining a common Asian lineage ofMycobacterium tuberculosisassociates with immune subversion

Diverse regulatory roles for lysosomal proteases in the immune response

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