Is Interleukin-4δ3 Splice Variant Expression in Bovine Tuberculosis a Marker of Protective Immunity?

Rhodes, Shelley; Sawyer, Jason; Whelan, Adam O.; Dean, Gillian S.; Coad, Michael; Ewer, Katie; Waldvogel, Andreas; Zakher, A.; Clifford, Derek; Hewinson, R. Glyn; Vordermeier, H. Martin

doi:10.1128/iai.01932-06

Cited by 21 publications

(16 citation statements)

References 38 publications

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“…Despite these issues, it has long been observed that subsets of cattle highly exposed to M. bovis do not get infected. Cattle with M. bovis ‐purified protein derivative (PPD)‐negative skin tests, with no visible lesions found in slaughter, are then confirmed by histopathology and culture as M. bovis ‐negative 19 , 20 , 21 . This supports the previous notion that some individuals of the cattle population can overcome an infective challenge of M. bovis.…”

supporting

confidence: 73%

Divergent macrophage responses to Mycobacterium bovis among naturally exposed uninfected and infected cattle

Alcaraz‐López¹,

García-Gil²,

Morales-Martínez³

et al. 2017

Immunol Cell Biol

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Mycobacterium bovis, the causative agent of bovine tuberculosis (TB), is a successful pathogen that remains an important global threat to livestock. Cattle naturally exposed to M. bovis normally become reactive to the M. bovis-purified protein derivative (tuberculin) skin test; however, some individuals remain negative, suggesting that they may be resistant to infection. To better understand host innate resistance to infection, 26 cattle from herds with a long history of high TB prevalence were included in this study. We investigated the bactericidal activity, the production of reactive oxygen and nitrogen species and the TB-related gene expression profile after in vitro M. bovis challenge of monocyte-derived macrophages from cattle with TB (n=17) and from non-infected, exposed cattle (in-contacts, n=9). The disease status was established based on the tuberculin skin test and blood interferon-gamma test responses, the presence of visible lesions at inspection on abattoirs and the histopathology and culture of M. bovis. Although macrophages from TB-infected cattle enabled M. bovis replication, macrophages from healthy, exposed cattle had twofold lower bacterial loads, overproduced nitric oxide and had lower interleukin (IL)-10 gene expression (P⩽0.05). Higher mRNA expression levels of inducible nitric oxide synthase, C-C motif chemokine ligand 2 and IL-12 were observed in macrophages from all in-contact cattle than in macrophages from their TB-infected counterparts, which expressed more tumour necrosis factor-α; however, the differences were not statistically significant owing to individual variation. These results confirm that macrophage bactericidal responses have a crucial role in innate resistance to M. bovis infection in cattle.

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supporting

confidence: 73%

Divergent macrophage responses to Mycobacterium bovis among naturally exposed uninfected and infected cattle

Alcaraz‐López¹,

García-Gil²,

Morales-Martínez³

et al. 2017

Immunol Cell Biol

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“…Many alternative splicing variants including IL-2, IL-4, IL-6, IL-7, and mast cell growth factor have been identified (36–39). IL-4 alternative splicing takes place not only in humans (6), but also in other species including chimpanzee (40), European rabbit (41), mouse (42), and cattle (43, 44). The fact that VIL-4 mRNA is identified in cells from lymphoid tissues in some M. tuberculosis -infected and BCG-infected monkeys suggests that host factors play a role in selection of such variant mRNA during mycobacterial infection.…”

Section: Discussionmentioning

confidence: 99%

Tuberculosis-Induced Variant IL-4 mRNA Encodes a Cytokine Functioning As Growth Factor for (E)-4-Hydroxy-3-Methyl-But-2-Enyl Pyrophosphate-Specific Vγ2Vδ2 T Cells

Yuan

Wang

Lee

et al. 2009

The Journal of Immunology

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The possibility that mycobacterial infections induce variant cytokine mRNA encoding a functionally distinct protein for immune regulation has not been addressed. In this study, we reported that Mycobacterium tuberculosis and bacillus Calmette-Guérin infections of macaques induced expression of variant IL-4 (VIL-4) mRNA encoding a protein comprised of N-terminal 97 aa identical with IL-4, and unique C-terminal 96 aa including a signaling-related proline-rich motif. While VIL-4 could be stably produced as intact protein, the purified VIL-4 induced apparent expansion of phosphoantigen (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate (HMBPP)-specific Vγ2Vδ2 T cells in dose- and time-dependent manners. The unique C-terminal 96 aa bearing the proline-rich motif (PPPCPP) of VIL-4 appeared to confer the ability to expand Vγ2Vδ2 T cells, since simultaneously produced IL-4 had only a subtle effect on these γδ T cells. Moreover, VIL-4 seemed to use IL-4R α for signaling and activation, as the VIL-4-induced expansion of Vγ2Vδ2 T cells was blocked by anti-IL-4R α mAb but not anti-IL-4 mAb. Surprisingly, VIL-4-expanded Vγ2Vδ2 T cells after HMBPP stimulation appeared to be heterologous effector cells capable of producing IL-4, IFN-γ, and TNF-α. Thus, mycobacterial infections of macaques induced variant mRNA encoding VIL-4 that functions as growth factor promoting expansion of HMBPP-specific Vγ2Vδ2 T effector cells.

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“…The resulting transcript and the corresponding protein isoform were dubbed IL-4␦2 [19 -22]. Minimal information is available about other splice variants of IL-4 [23,24], the discussion of which goes beyond the scope of this review article.…”

Section: Splice Variants Of Il-4mentioning

confidence: 99%

Regulation of inflammation by interleukin-4: a review of “alternatives”

Luzina

Keegan

Heller

et al. 2012

Journal of Leukocyte Biology

305

196

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Is Interleukin-4δ3 Splice Variant Expression in Bovine Tuberculosis a Marker of Protective Immunity?

Cited by 21 publications

References 38 publications

Divergent macrophage responses to Mycobacterium bovis among naturally exposed uninfected and infected cattle

Divergent macrophage responses to Mycobacterium bovis among naturally exposed uninfected and infected cattle

Tuberculosis-Induced Variant IL-4 mRNA Encodes a Cytokine Functioning As Growth Factor for (E)-4-Hydroxy-3-Methyl-But-2-Enyl Pyrophosphate-Specific Vγ2Vδ2 T Cells

Regulation of inflammation by interleukin-4: a review of “alternatives”

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