The Adaptor Protein Bam32 in Human Dendritic Cells Participates in the Regulation of MHC Class I-Induced CD8+ T Cell Activation

Ortner, Daniela; Grabher, Daniela; Hermann, Michael; Kremmer, Elisabeth; Hofer, Susanne; Heufler, Christine

doi:10.4049/jimmunol.1003072

Cited by 13 publications

(8 citation statements)

References 41 publications

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“…The GxE locus we identified on chromosome 3 in response to DEP contained several genes without an obvious role in lung function or asthma-related traits. Of these, we prioritized Dapp1 because of its known role in mediating activation of and interactions between immune cells [65][66][67][68][69], its expression profile in tissues relevant to asthma, and the high correlation of its mRNA levels with those of several asthma-related inflammatory cytokines in humans. In two independent experiments with genetically targeted mice, we functionally validated Dapp1 as an exposure-responsive gene at the chromosome 3 locus.…”

Section: Fig 5 Functional Validation Of Dapp1 As a Dep-responsive Gementioning

confidence: 99%

A GWAS approach identifies Dapp1 as a determinant of air pollution-induced airway hyperreactivity

et al. 2019

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Asthma is a chronic inflammatory disease of the airways with contributions from genes, environmental exposures, and their interactions. While genome-wide association studies (GWAS) in humans have identified~200 susceptibility loci, the genetic factors that modulate risk of asthma through gene-environment (GxE) interactions remain poorly understood. Using the Hybrid Mouse Diversity Panel (HMDP), we sought to identify the genetic determinants of airway hyperreactivity (AHR) in response to diesel exhaust particles (DEP), a model traffic-related air pollutant. As measured by invasive plethysmography, AHR under control and DEP-exposed conditions varied 3-4-fold in over 100 inbred strains from the HMDP. A GWAS with linear mixed models mapped two loci significantly associated with lung resistance under control exposure to chromosomes 2 (p = 3.0x10-6) and 19 (p = 5.6x10-7). The chromosome 19 locus harbors Il33 and is syntenic to asthma association signals observed at the IL33 locus in humans. A GxE GWAS for post-DEP exposure lung resistance identified a significantly associated locus on chromosome 3 (p = 2.5x10-6). Among the genes at this locus is Dapp1, an adaptor molecule expressed in immune-related and mucosal tissues, including the lung. Dapp1-deficient mice exhibited significantly lower AHR than control mice but only after DEP exposure, thus functionally validating Dapp1 as one of the genes underlying the GxE association at this locus. In summary, our results indicate that some of the genetic determinants for asthma-related phenotypes may be shared between mice and humans, as well as the existence of GxE interactions in mice that modulate lung function in response to air pollution exposures relevant to humans.

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Section: Fig 5 Functional Validation Of Dapp1 As a Dep-responsive Gementioning

confidence: 99%

A GWAS approach identifies Dapp1 as a determinant of air pollution-induced airway hyperreactivity

et al. 2019

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“…Indeed, galectin-1 imparts a regulatory program in dendritic cells, resulting in lower lymphocyte priming [ 177 , 178 ]. However, regulation of the dendritic cell properties by galectin-1 does not exclusively depend on the extracellular concentrations of this lectin since endogenous galectin-1 also controls dendritic cell immunogenic potential [ 177 , 179 , 180 ]. Altogether, galectin-1 plays an essential role in controlling the initial steps of antigen-specific lymphocyte activation.…”

Section: Introductionmentioning

confidence: 99%

Unraveling How Tumor-Derived Galectins Contribute to Anti-Cancer Immunity Failure

Laderach

Compagno

2021

Cancers

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Current data indicates that anti-tumor T cell-mediated immunity correlates with a better prognosis in cancer patients. However, it has widely been demonstrated that tumor cells negatively manage immune attack by activating several immune-suppressive mechanisms. It is, therefore, essential to fully understand how lymphocytes are activated in a tumor microenvironment and, above all, how to prevent these cells from becoming dysfunctional. Tumors produce galectins-1, -3, -7, -8, and -9 as one of the major molecular mechanisms to evade immune control of tumor development. These galectins impact different steps in the establishment of the anti-tumor immune responses. Here, we carry out a critical dissection on the mechanisms through which tumor-derived galectins can influence the production and the functionality of anti-tumor T lymphocytes. This knowledge may help us design more effective immunotherapies to treat human cancers.

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“…Bam32 in mast cells inhibits FcƐRI-induced calcium flux and granule release by activating Lyn and SHIP negative signaling pathways [13]. Furthermore, Bam32 in DC is located at the DCT cell contact sites and binds to galectin-1 to suppress the FOXP3 + -induced proliferation of T cells [14]. Bam32 is expressed at similar levels in mouse neutrophils as in B cells [15].…”

Section: Introductionmentioning

confidence: 99%

Suppressive Role of Bam32/DAPP1 in Chemokine-Induced Neutrophil Recruitment

Marshall

Liu

2021

IJMS

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Bam32 (B cell adaptor molecule of 32 kDa) functions in the immune responses of various leukocytes. However, the role of neutrophil Bam32 in inflammation is entirely unknown. Here, we determined the role of Bam32 in chemokine CXCL2-induced neutrophil chemotaxis in three mouse models of neutrophil recruitment. By using intravital microscopy in the mouse cremaster muscle, we found that transmigrated neutrophil number, neutrophil chemotaxis velocity, and total neutrophil chemotaxis distance were increased in Bam32−/− mice when compared with wild-type (WT) mice. In CXCL2-induced mouse peritonitis, the total emigrated neutrophils were increased in Bam32−/− mice at 2 but not 4 h. The CXCL2-induced chemotaxis distance and migration velocity of isolated Bam32−/− neutrophils in vitro were increased. We examined the activation of small GTPases Rac1, Rac2, and Rap1; the levels of phospho-Akt2 and total Akt2; and their crosstalk with Bam32 in neutrophils. The deficiency of Bam32 suppressed Rap1 activation without changing the activation of Rac1 and Rac2. The pharmacological inhibition of Rap1 by geranylgeranyltransferase I inhibitor (GGTI298) increased WT neutrophil chemotaxis. In addition, the deficiency of Bam32, as well as the inhibition of Rap1 activation, increased the levels of CXCL2-induced Akt1/2 phosphorylation at Thr308/309 in neutrophils. The inhibition of Akt by SH-5 attenuated CXCL2-induced adhesion and emigration in Bam32−/− mice. Together, our results reveal that Bam32 has a suppressive role in chemokine-induced neutrophil chemotaxis by regulating Rap1 activation and that this role of Bam32 in chemokine-induced neutrophil recruitment relies on the activation of PI3K effector Akt.

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The Adaptor Protein Bam32 in Human Dendritic Cells Participates in the Regulation of MHC Class I-Induced CD8+ T Cell Activation

Cited by 13 publications

References 41 publications

A GWAS approach identifies Dapp1 as a determinant of air pollution-induced airway hyperreactivity

A GWAS approach identifies Dapp1 as a determinant of air pollution-induced airway hyperreactivity

Unraveling How Tumor-Derived Galectins Contribute to Anti-Cancer Immunity Failure

Suppressive Role of Bam32/DAPP1 in Chemokine-Induced Neutrophil Recruitment

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