Batf2 differentially regulates tissue immunopathology in Type 1 and Type 2 diseases

Guler, Reto; Mpotje, Thabo; Ozturk, Mumin; Nono, Justin Komguep; Parihar, Suraj P.; Chia, Julius Ebua; Aziz, Nada Abdel; Hlaka, Lerato; Kumar, Santosh; Roy, Sugata; Penn-Nicholson, Adam; Hanekom, Willem A.; Zak, Daniel E.; Scriba, Thomas J.; Suzuki, Harukazu; Brombacher, Frank

doi:10.1038/s41385-018-0108-2

Cited by 25 publications

(20 citation statements)

References 45 publications

(56 reference statements)

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“…We previously demonstrated that Batf2 was expressed in CD11b + F4/80 + macrophages (Mϕs) in the spleen, but not adaptive lymphoid cells, and that it contributed to the suppression of immunopathological T h 17 responses during T. cruzi infection (37). A recent study clearly demonstrated that Batf2 expression induced in Mϕs in the lung during infection with M. tuberculosis and Listeria monocytogenes was associated with the pathogenesis of type 1 infectious diseases (43). In addition, this study showed that BATF2 contributed to prevention of type 2 infectious disease caused by Schistosoma mansoni infection in the small intestine.…”

Section: Resultsmentioning

confidence: 99%

BATF2 prevents T-cell-mediated intestinal inflammation through regulation of the IL-23/IL-17 pathway

Kayama

Tani

Kitada

et al. 2019

International Immunology

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Inappropriate activation of the IL-23 signaling pathway causes chronic inflammation through the induction of immunopathological T h 17 cells in several tissues including the intestine, whereas adequate T h 17 responses are essential for host defense against harmful organisms. In the intestinal lamina propria, IL-23 is primarily produced by innate myeloid cells including dendritic cells (DCs) and macrophages (Mϕs). However, the molecular mechanisms underlying the regulation of IL-23 production by these cells remains poorly understood. In this study, we demonstrated that BATF2 regulates intestinal homeostasis by inhibiting IL-23-driven T-cell responses. Batf2 was highly expressed in intestinal innate myeloid subsets, such as monocytes, CD11b + CD64 + Mϕs and CD103 + DCs. Batf2 −/− mice spontaneously developed colitis and ileitis with altered microbiota composition. In this context, IL-23, but not TNF-α and IL-10, was produced in high quantities by intestinal CD11b + CD64 + Mϕs from Batf2 −/− mice compared with wild-type mice. Moreover, increased numbers of IFN-γ + , IL-17 + and IFN-γ + IL-17 + CD4 + T cells, but not IL-10 + CD4 + T cells, accumulated in the colons and small intestines of Batf2 −/− mice. In addition, RORγt-expressing innate lymphoid cells were increased in Batf2 −/− mice. Batf2 −/− Rag2 −/− mice showed a reduction in intestinal inflammation present in Batf2 −/− mice. Furthermore, the high numbers of intestinal IL-17 + and IFN-γ + IL-17 + CD4 + T cells were markedly reduced in Batf2 −/− mice when introducing Il23a deficiency, which was associated with the abrogation of intestinal inflammation. These results indicated that BATF2 in innate myeloid cells is a key molecule for the suppression of IL-23/IL-17 pathway-mediated adaptive intestinal pathology.

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Section: Resultsmentioning

confidence: 99%

BATF2 prevents T-cell-mediated intestinal inflammation through regulation of the IL-23/IL-17 pathway

Kayama

Tani

Kitada

et al. 2019

International Immunology

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“…BATF2 is predominantly expressed in monocytes and macrophages and has a central role in macrophage activation by regulating inflammatory responses during mycobacterial infection. In human tuberculosis (TB), BAFT2 has been suggested as a biomarker and a potential host directed drug target 31,32 . The CXCL10 chemokine, also known as IFN-γ inducible protein-10 ( IP-10 ), is chemotactic for monocytes and T-lymphocytes by binding to CXCR3 receptor.…”

Section: Discussionmentioning

confidence: 99%

RNA-Seq analysis of ileocecal valve and peripheral blood from Holstein cattle infected with Mycobacterium avium subsp. paratuberculosis revealed dysregulation of the CXCL8/IL8 signaling pathway

Alonso‐Hearn

Canive

Blanco‐Vázquez

et al. 2019

Sci Rep

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Paratuberculosis is chronic granulomatous enteritis of ruminants caused by Mycobacterium avium subsp. paratuberculosis (MAP). Whole RNA-sequencing (RNA-Seq) is a promising source of novel biomarkers for early MAP infection and disease progression in cattle. Since the blood transcriptome is widely used as a source of biomarkers, we analyzed whether it recapitulates, at least in part, the transcriptome of the ileocecal valve (ICV), the primary site of MAP colonization. Total RNA was prepared from peripheral blood (PB) and ICV samples, and RNA-Seq was used to compare gene expression between animals with focal or diffuse histopathological lesions in gut tissues versus control animals with no detectable signs of infection. Our results demonstrated both shared, and PB and ICV-specific gene expression in response to a natural MAP infection. As expected, the number of differentially expressed (DE) genes was larger in the ICV than in the PB samples. Among the DE genes in the PB and ICV samples, there were some common genes irrespective of the type of lesion including the C-X-C motif chemokine ligand 8 (CXCL8/IL8), apolipoprotein L (APOLD1), and the interferon inducible protein 27 (IFI27). The biological processes (BP) enriched in the PB gene expression profiles from the cows with diffuse lesions included the killing of cells of other organism, defense response, immune response and the regulation of neutrophil chemotaxis. Two of these BP, the defense and immune response, were also enriched in the ICV from the cows with diffuse lesions. Metabolic analysis of the DE genes revealed that the N-glycan biosynthesis, bile secretion, one-carbon pool by folate and purine metabolism were significantly enriched in the ICV from the cows with focal lesions. In the ICV from cows with diffuse lesions; the valine, leucine and isoleucine degradation route, purine metabolism, vitamin digestion and absorption and the cholesterol routes were enriched. Some of the identified DE genes, BP and metabolic pathways will be studied further to develop novel diagnostic tools, vaccines and immunotherapeutics.

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“…Genes in the 16-gene ACS signature that mediate detrimental effects during infection of mice-Of the 16-gene ACS signature genes analyzed for functional relevance in mice, we identified three genes (Batf2, Fcgr1, and Scarf1) which contribute to Mtb susceptibility at distinct phases of infection. BATF2 is a basic leucine zipper transcription factor that is closely related to BATF and BATF3 (46), which together regulate dendritic cell differentiation and development. Batf2/3 −/− mice were more resistant to Mtb infection and unexpectedly showed improved Mtb control upon infection during the transition from acute to chronic stages at 60 and 100 dpi (Fig.…”

Section: Delineating the Functional Relevance Of Genes In The 16-genementioning

confidence: 99%

Immune correlates of tuberculosis disease and risk translate across species

et al. 2020

Self Cite

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One quarter of the world’s population is infected with Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB). Although most infected individuals successfully control or clear the infection, some individuals will progress to TB disease. Immune correlates identified using animal models are not always effectively translated to human TB, thus resulting in a slow pace of translational discoveries from animal models to human TB for many platforms including vaccines, therapeutics, biomarkers, and diagnostic discovery. Therefore, it is critical to improve our poor understanding of immune correlates of disease and protection that are shared across animal TB models and human TB. In this study, we have provided an in-depth identification of the conserved and diversified gene/immune pathways in TB models of nonhuman primate and diversity outbred mouse and human TB. Our results show that prominent differentially expressed genes/pathways induced during TB disease progression are conserved in genetically diverse mice, macaques, and humans. In addition, using gene-deficient inbred mouse models, we have addressed the functional role of individual genes comprising the gene signature of disease progression seen in humans with Mtb infection. We show that genes representing specific immune pathways can be protective, detrimental, or redundant in controlling Mtb infection and translate into identifying immune pathways that mediate TB immunopathology in humans. Together, our cross-species findings provide insights into modeling TB disease and the immunological basis of TB disease progression.

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Batf2 differentially regulates tissue immunopathology in Type 1 and Type 2 diseases

Cited by 25 publications

References 45 publications

BATF2 prevents T-cell-mediated intestinal inflammation through regulation of the IL-23/IL-17 pathway

BATF2 prevents T-cell-mediated intestinal inflammation through regulation of the IL-23/IL-17 pathway

RNA-Seq analysis of ileocecal valve and peripheral blood from Holstein cattle infected with Mycobacterium avium subsp. paratuberculosis revealed dysregulation of the CXCL8/IL8 signaling pathway

Immune correlates of tuberculosis disease and risk translate across species

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