DC ElementWertSprache
dc.contributor.advisorNeumann, Katrin-
dc.contributor.authorLinke, Alexandra-
dc.date.accessioned2023-03-13T11:03:54Z-
dc.date.available2023-03-13T11:03:54Z-
dc.date.issued2022-
dc.identifier.urihttps://ediss.sub.uni-hamburg.de/handle/ediss/10137-
dc.description.abstractDuring glomerulonephritis (GN), T cells infiltrate the kidney and accumulate mainly in the tubulointerstitium close to proximal tubular epithelial cells (PTECs). Different T cell subsets were shown to have either a pro-inflammatory or an immune-regulatory role in GN. The role of PTECs as kidney-intrinsic cells in GN pathology is less clear. PTECs were shown to be non-professional antigen presenting cells (APCs) in the kidney, expressing proteins connected with antigen presentation, such as MHC-II, CD74 and the co-stimulatory molecules CD80 and CD86 and presented exogenous antigen to CD4+ T cells via MHC-II, thereby activating them and leading to pro-inflammatory cytokine expression in CD4+ T cells (Breda et al. 2019). If PTECs are able to cross-present exogenous antigen via MHC-I, thereby leading to CD8+ T cell activation, is less clear. This study analyzes the capacity of PTECs for antigen cross-presentation in in vitro co-culture experiments with OVA-specific CD8+ T cells using OVA as antigen. Gene and protein expression analysis showed that PTECs express proteins crucial for antigen cross-presentation, such as the MR, the transport channel Sec61, the ATPase VCP, LMP7, a subunit of the immunoproteasome, and TAP transporters. Moreover, using MR- and clathrin-inhibitors, this study reveals that PTECs internalize antigen via MR-dependent endocytosis. CD8+ T cells were co-cultured with PTECs, LSECs as non-professional APCs from liver or DCs as professional APCs and the phenotype of CD8+ T cells was analyzed after 2.5 and 5 days of co-culture. After 2.5 days, all three APC types induced T cell activation, proliferation and expression of pro-inflammatory and cytotoxicity-associated molecules. After 5 days, the phenotype of DC- and PTEC-activated CD8+ T cells was similar to the phenotype after 2.5 days, whereas LSEC-activated CD8+ T cells did not proliferate, lost IL-2 expression and showed strongly reduced expression of IFNγ or GzmB. Consequently, while LSECs contribute to a tolerogenic phenotype of CD8+ T cells via antigen cross-presentation, PTECs induce inflammation and cytotoxicity. A cytotoxicity assay showed that PTEC-activated CD8+ T cells exerted cytotoxic function by killing allogeneic target cells. Pre-treatment of PTECs with the LMP7 inhibitor ONX 0914 reduced CD8+ T cell activation by PTECs. Moreover, proteasomal subunit expression analysis and the use of ABPs revealed that PTECs use both the immunoproteasome and the constitutive proteasome for antigen cross-presentation. CD8/ CD3 staining of renal tissue showed mainly tubulointerstitial and only minor intraglomerular CD8+ T cell accumulation in murine lupus nephritis. Apoptotic cell death was analyzed in nephritic kidneys of pristane-treated mice and showed especially TECs to be apoptotic. The absence of CD8+ T cells in Cd8-/- mice resulted in reduced apoptosis of TECs. In MRL-lpr mice lacking the Fas/FasL pathway for induction of cell death, the number of apoptotic cells was reduced compared to control mice. In a nutshell, this study depicts PTECs to be potent antigen cross-presenters, thereby inducing inflammatory and cytotoxic CD8+ T cells. Moreover, CD8+ T cells are shown to mediate induction of tubular apoptosis in murine lupus nephritis.en
dc.language.isoende_DE
dc.publisherStaats- und Universitätsbibliothek Hamburg Carl von Ossietzkyde
dc.rightshttp://purl.org/coar/access_right/c_abf2de_DE
dc.subjectantigen cross-presentationen
dc.subjectcytotoxic CD8+ T cellsen
dc.subjectlupus nephritisen
dc.subjectproximal tubular epithelial cellsen
dc.subjectapoptosisen
dc.subjectAntigen Kreuz-Präsentationde
dc.subjectZytotoxische CD8+ T Zellende
dc.subjectLupusnephritisde
dc.subjectProximale Tubulusepithelzellende
dc.subjectApoptosede
dc.subject.ddc610: Medizinde_DE
dc.titleAntigen Cross-Presentation by Murine Proximal Tubular Epithelial Cells Induces Cytotoxic and Inflammatory CD8+ T Cellsen
dc.title.alternativeAntigen Kreuz-Präsentation durch Murine Proximale Tubulusepithelzellen Induziert Cytotoxische und Inflammatorische CD8+ T Zellende
dc.typedoctoralThesisen
dcterms.dateAccepted2023-02-28-
dc.rights.cchttps://creativecommons.org/licenses/by/4.0/de_DE
dc.rights.rshttp://rightsstatements.org/vocab/InC/1.0/-
dc.type.casraiDissertation-
dc.type.dinidoctoralThesis-
dc.type.driverdoctoralThesis-
dc.type.statusinfo:eu-repo/semantics/publishedVersionde_DE
dc.type.thesisdoctoralThesisde_DE
tuhh.type.opusDissertation-
thesis.grantor.departmentMedizinde_DE
thesis.grantor.placeHamburg-
thesis.grantor.universityOrInstitutionUniversität Hamburgde_DE
dcterms.DCMITypeText-
dc.identifier.urnurn:nbn:de:gbv:18-ediss-107679-
item.advisorGNDNeumann, Katrin-
item.grantfulltextopen-
item.languageiso639-1other-
item.fulltextWith Fulltext-
item.creatorOrcidLinke, Alexandra-
item.creatorGNDLinke, Alexandra-
Enthalten in den Sammlungen:Elektronische Dissertationen und Habilitationen
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