Der Einfluss der Transkriptionsfaktoren IRF4 und IRF9 auf die CD8+ T-zell-vermittelte Immunantwort während der Infektion mit intrazellulären Erregern
Interferon Regulierende Faktoren (IRF) sind Transkriptionsfaktoren (TF), die vielfältige Funktionen in der Regulation der angeborenen und adaptiven Immunantwort besitzen. Im Zusammenspiel miteinander oder mit weiteren TF regulieren sie die Genexpression. Die essentielle Rolle von IRF4 für die Differ...
Hygiene u. Med. Mikrobiologie mit Medizinaluntersuchungsamt
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- The interferon regulatory factors (IRF) are transcription factors (TF) that possess a variety of functions in the regulation of innate and adaptive immunity, to regulate the gene expression in association with each other or with further TFs. IRF4 is crucial for the differentiation into distinct subsets of CD4+ and CD8+ T cells. IRF9 is ubiquitously expressed in cells. It functions as DNA binding domain in response to type I IFN in the transcriptional complex interferon-stimulated gene factor 3 (ISGF3) in association with signal transducer and activator of transcription (STAT) 1 and 2. Following infection with intracellular pathogens, CD8+ T cells become activated, proliferate rapidly und differentiate into cytotoxic T lymphocytes (CTLs). After clearance of pathogens only a limited number of effector cells survive and develop into long-lived memory cells. During chronic infections activated CD8+ T cells may become exhausted, what is characterized by impaired functions and incapability to form conventional memory CD8+ T cells. Infections with lymphocytic chorimeningitis virus (LCMV) can be distinguished into chronic infections, caused by LCMV clone 13 and acute LCMV Armstrong (Arm) infections. In response to viral infections the transcriptional complex ISGF3, induced by canonical type I IFN signaling, binds to IFN-stimulated response element (ISRE) sequences to activate classical antiviral genes (ISGs) and it is known, that both Stat1-/- and Stat2-/- mice are highly susceptible to viral infections. The first part of this thesis investigated the influence of IRF4 for CD8+ T cells during an immune response against the intracellular bacterium Listeria monocytogenes (Lm). Irf4 /- mice showed partially impaired clearance of Listeria infection, which was due to a reduced CD8+ T cell response. Antigen-specific Irf4 /- CD8+ T cells showed limited accumulation in different organs and these cells also displayed an altered effector phenotype as well as impaired effector function. Transfer experiments revealed that IRF4 functions in CD8+ T cells in a cell intrinsic manner. In line with these observed defects, Irf4-/- CD8+ T cells showed reduced levels of TF associated with effector cell differentiation, such as Prdm1, Tbx21 and Id2. Furthermore it was shown that IRF4 bound to an IL-21 responsive element downstream of Prdm1 (encoding BLIMP1) suggesting that regulation of BLIMP1 by IRF4 contributes to the generation of CD8+ effector cells. It is likely that IRF4 is also essential for memory cell generation, because Irf4-/- CD8+ T cells also showed impaired memory formation. The second part focused on the IRF9-dependency of the antiviral CD8+ T cell response. Upon infection with LCMV Arm, Irf9-/- mice developed chronic disease in contrast to WT mice. This was accompanied by an exhausted phenotype of pathogen-specific CD8+ T cells in Irf9-/- mice. As a result Irf9-/- mice developed reduced numbers of LCMV-specific CD8+ T cells with diminished expression of the activation marker KLRG1, and with impaired production of the effector cytokines TNFα and IFNγ. In accordance with these results Irf9-/- CD8+ T cells strongly upregulated the inhibitory receptors PD-1 and LAG-3. IRF9 is also involved in the positive regulation of the expression of the TF TBX21, which promotes terminal differentiation of CD8+ effector T cells and prevents exhaustion of CD8+ T cells during chronic infection by direct repression of PD-1 and regulation of LAG-3 expression. In conclusion the results of this PhD thesis identified a key role for IRF4 in the generation of functional effector CD8+ T cells, while IRF9 protects CD8+ T cells from exhaustion during acute LCMV infection.