Adoptively transferred in vitro-generated MDSCs improve T cell function and antigen-specific immunity after blunt chest trauma-induced lung injury
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE188171 | GEO | 2022/06/16
REPOSITORIES: GEO
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Project description:Myeloid-derived suppressor cells (MDSCs) expand during inflammation and exhibit immunomodulatory functions on innate and adaptive immunity. However, their impact on trauma-induced immune responses, characterized by an early pro-inflammatory phase and dysregulated adaptive immunity involving lymphocyte apoptosis, exhaustion and unresponsiveness is less clear. Therefore, we adoptively transferred in vitro-generated MDSCs shortly before experimental blunt chest trauma (TxT). MDSCs preferentially homed into spleen and liver, but were undetectable in the injured lung, although pro-inflammatory mediators transiently increased in the bronchoalveolar lavage (BAL). Surprisingly, MDSC treatment strongly increased splenocyte numbers, however, without altering the percentage of splenic leukocyte populations. T cells of MDSC-treated TxT mice exhibited an activated phenotype characterized by expression of activation markers and elevated proliferative capacity in vitro, which was not accompanied by up-regulated exhaustion markers or unresponsiveness towards in vitro activation. Most importantly, also T cell expansion after staphylococcal enterotoxin B (SEB) stimulation in vivo was unchanged between MDSC-treated or untreated mice. After MDSC transfer, T cells preferentially exhibited a Th1 phenotype, a prerequisite to circumvent post-traumatic infectious complications. Our findings reveal a totally unexpected immunostimulatory role of adoptively transferred MDSCs in TxT and might offer options to interfere with post-traumatic malfunction of the adaptive immune response.
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Project description:Adoptively transferred in vitro-generated MDSCs improve T cell function and antigen-specific immunity after blunt chest trauma-induced lung injury
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Project description:C. elegans exhibit an age-dependent mechanical stress response to blunt force injury. Stress responses are often defined in part by an elicited cellular transcriptional response. We find in C. elegans that mechanical stress by blunt trauma induces a distinct and age-dependent transcriptional program.
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Project description:The selective vulnerability of dopaminergic neurons to trauma-induced neurodegeneration is a conserved phenomenon across species, extending from nematodes to humans. However, the molecular mechanisms contributing to this hypersensitivity to blunt force injury remain poorly understood. We find that dopamine oxidation, a key driver of Parkinson’s Disease, extends its toxic role to the acute challenges of blunt force trauma. Ectopic synthesis of dopamine in serotonergic neurons alone proves sufficient in determining neuronal subtype sensitivity to trauma-induced death. While dopaminergic neurons maintain this neurotransmitter in a functional and benign state, trauma-induced subcellular redox imbalances elicit dopamine-dependent cytotoxicity. Perturbing dopamine synthesis and its packaging into synaptic vesicles further demonstrate how cytosolic dopamine is both necessary and sufficient to drive cell loss upon mechanical stress and during aging. Additionally, trauma activates the B-Zip transcription factor, fos-1, which exacerbates this toxic cascade by transcriptionally upregulating the rate-limiting enzyme in dopamine synthesis, cat-2. In summary, our study unravels the molecular intricacies that render dopaminergic neurons uniquely prone to physical perturbation, highlighting a shared vulnerability across different evolutionary lines.
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Project description:The selective vulnerability of dopaminergic neurons to trauma-induced neurodegeneration is a conserved phenomenon across species, extending from nematodes to humans. However, the molecular mechanisms contributing to this hypersensitivity to blunt force injury remain poorly understood. We find that dopamine oxidation, a key driver of Parkinson’s Disease, extends its toxic role to the acute challenges of blunt force trauma. Ectopic synthesis of dopamine in serotonergic neurons alone proves sufficient in determining neuronal subtype sensitivity to trauma-induced death. While dopaminergic neurons maintain this neurotransmitter in a functional and benign state, trauma-induced subcellular redox imbalances elicit dopamine-dependent cytotoxicity. Perturbing dopamine synthesis and its packaging into synaptic vesicles further demonstrate how cytosolic dopamine is both necessary and sufficient to drive cell loss upon mechanical stress and during aging. Additionally, trauma activates the B-Zip transcription factor, fos-1, which exacerbates this toxic cascade by transcriptionally upregulating the rate-limiting enzyme in dopamine synthesis, cat-2. In summary, our study unravels the molecular intricacies that render dopaminergic neurons uniquely prone to physical perturbation, highlighting a shared vulnerability across different evolutionary lines.
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Project description:Severe blunt chest trauma (TxT) induces a strong inflammatory response with posttraumatic immune suppression pointing to an impaired adaptive immune response. Since CD11b+Gr-1+-expressing myeloid-derived suppressor cells (MDSCs) are induced after inflammation and suppress T cell responses, MDSC induction and their impact on T cell functions was analysed in an experimental TxT model. MDSCs were induced preferentially in the lung until 24 hours after TxT. Although MDSC numbers were only faintly increased in the spleen, splenic MDSCs isolated after TxT strongly inhibited alloantigen-induced T cell proliferation in vitro. Suppressive activity correlated with increased expression of arginase-1 and iNOS. MDSCs also prevented antigen-induced T cell expansion in vivo, since staphylococcus enterotoxin B (SEB)-induced proliferation of vβ8+ T cells was impaired in TxT mice in the presence of CD11b+Gr-1+ cells. Surprisingly, MDSCs were not involved in shifting T cells into Th2 cells, characterized by the secretion of cytokines impairing cell-mediated immunity and promoting immunosuppression. Instead, the presence of CD11b+Gr-1+ cells was required for efficient IL-2, IFN-γ and TNFα production after antigenic stimulation, indicating, that elevation of MDSCs early after traumatic injuries might contribute to restrict the initial inflammatory response by alleviating T cell expansion, however, without impeding Th1 functions.
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