Browsing by Subject "T cell activation"

Now showing 1 - 3 of 3
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    Control of the temporal development of Alzheimer's disease pathology by the MR1/MAIT cell axis
    (BMC, 2023-03-21) Wyatt‑Johnson, Season K.; Kersey, Holly N.; Codocedo, Juan F.; Newell, Kathy L.; Landreth, Gary E.; Lamb, Bruce T.; Oblak, Adrian L.; Brutkiewicz, Randy R.; Microbiology and Immunology, School of Medicine
    Background: Neuroinflammation is an important feature of Alzheimer's disease (AD). Understanding which aspects of the immune system are important in AD may lead to new therapeutic approaches. We study the major histocompatibility complex class I-related immune molecule, MR1, which is recognized by an innate-like T cell population called mucosal-associated invariant T (MAIT) cells. Methods: Having found that MR1 gene expression is elevated in the brain tissue of AD patients by mining the Agora database, we sought to examine the role of the MR1/MAIT cell axis in AD pathology. Brain tissue from AD patients and the 5XFAD mouse model of AD were used to analyze MR1 expression through qPCR, immunofluorescence, and flow cytometry. Furthermore, mice deficient in MR1 and MAIT cells were crossed with the 5XFAD mice to produce a model to study how the loss of this innate immune axis alters AD progression. Moreover, 5XFAD mice were also used to study brain-resident MAIT cells over time. Results: In tissue samples from AD patients and 5XFAD mice, MR1 expression was substantially elevated in the microglia surrounding plaques vs. those that are further away (human AD: P < 0.05; 5XFAD: P < 0.001). In 5XFAD mice lacking the MR1/MAIT cell axis, the development of amyloid-beta plaque pathology occurred at a significantly slower rate than in those mice with MR1 and MAIT cells. Furthermore, in brain tissue from 5XFAD mice, there was a temporal increase in MAIT cell numbers (P < 0.01) and their activation state, the latter determined by detecting an upregulation of both CD69 (P < 0.05) and the interleukin-2 receptor alpha chain (P < 0.05) via flow cytometry. Conclusions: Together, these data reveal a previously unknown role for the MR1/MAIT cell innate immune axis in AD pathology and its potential utility as a novel therapeutic target.
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    Donor lung derived myeloid and plasmacytoid dendritic cells differentially regulate T cell proliferation and cytokine production
    (Springer Nature, 2012-03-20) Benson, Heather L.; Suzuki, Hidemi; Lott, Jeremy; Fisher, Amanda Jo; Walline, Crystal; Heidler, Kathleen M.; Brutkiewicz, Randy; Blum, Janice S.; Wilkes, David S.; Medicine, School of Medicine
    Background: Direct allorecognition, i.e., donor lung-derived dendritic cells (DCs) stimulating recipient-derived T lymphocytes, is believed to be the key mechanism of lung allograft rejection. Myeloid (cDCs) and plasmacytoid (pDCs) are believed to have differential effects on T cell activation. However, the roles of each DC type on T cell activation and rejection pathology post lung transplantation are unknown. Methods: Using transgenic mice and antibody depletion techniques, either or both cell types were depleted in lungs of donor BALB/c mice (H-2(d)) prior to transplanting into C57BL/6 mice (H-2(b)), followed by an assessment of rejection pathology, and pDC or cDC-induced proliferation and cytokine production in C57BL/6-derived mediastinal lymph node T cells (CD3+). Results: Depleting either DC type had modest effect on rejection pathology and T cell proliferation. In contrast, T cells from mice that received grafts depleted of both DCs did not proliferate and this was associated with significantly reduced acute rejection scores compared to all other groups. cDCs were potent inducers of IFNγ, whereas both cDCs and pDCs induced IL-10. Both cell types had variable effects on IL-17A production. Conclusion: Collectively, the data show that direct allorecognition by donor lung pDCs and cDCs have differential effects on T cell proliferation and cytokine production. Depletion of both donor lung cDC and pDC could prevent the severity of acute rejection episodes.
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    The Regulatory Role Of Matrix Metalloproteinases In T Cell Activation
    (2009-10) Benson, Heather Lynette; Wilkes, David S.
    Introduction: Matrix metalloproteinases (MMPs) are known for their role in extracellular matrix remodeling, but their role in regulating intracellular immune cell function is unknown. We reported that MMP inhibition down regulated T cell proliferation in response to alloantigens and autoantigens; but the direct role of MMP involvement in T cell activation has not been reported. Methods: MMP deficient or MMP sufficient wild-type CD4+ or CD8+ T cells from C57BL/6 mice were treated with SB-3CT, a specific inhibitor of MMP2 and MMP9, stimulated with anti-CD3 Ab, alone, or with IL-2 or CD28. Cellular activation and cytokine profiles were examined. A mouse model of antigen specific T cell mediated lung injury was used to examine MMP inhibition in antigen-specific T cell mediated lung injury. Results: SB-3CT (1-25μM) induced dose-dependent reductions in anti-CD3 Ab-induced proliferation (p<0.0001). Compared to wild-type, MMP9-/- CD4+ and CD8+ T cells proliferated 80-85% less (p<0.001) in response to anti-CD3 Ab. Compared to untreated or wild-type cells, anti-CD3 Ab-induced calcium flux was enhanced in SB-3CT-treated or MMP9-/- CD4+ and CD8+ T cells. Cytokine transcripts for IL-2, TNF-α and IFN-γ were reduced in both CD4+ and CD8+ MMP9-/- T cells, as well as in SB3CT treated CD4+ T cells. MMP inhibition dampened antigen-specific T cell mediated lung injury. Conclusions: Although known to be functional extracellularly, the current data suggest that MMPs function inside the cell to regulate intracellular signaling events involved in T cell activation. T cell targeted MMP inhibition may provide a novel approach of immune regulation in the treatment of T cell-mediated diseases. - David S. Wilkes, M.D., Chair.