Projektbeschreibung
Priming von T-Zellen: Auf das Timing kommt es an
Adaptive Immunantworten setzen ein, wenn dendritische Zellen den CD8-T-Zellen in sekundären lymphatischen Organen Antigene präsentieren. Ein Forschungsteam im EU-finanzierten Projekt STEP 2 will untersuchen, wie das Wanderverhalten von myeloischen und lymphatischen Zellen koordiniert wird, sodass sie sich zur richtigen Zeit am richtigen Ort begegnen. Mithilfe von Genomik, Transkriptomik und innovativer Bildgebung wollen die Forschenden diese spezielle Phase der Aktivierung und Differenzierung der T-Zellen entschlüsseln. Sobald die molekularen Determinanten dieser Phase adaptiver Immunität gefunden sind, werden sich neue Interventionen zur Auslösung einer Immunantwort gegen Krebs oder Infektionen entwickeln lassen.
Ziel
The initiation of adaptive cellular immunity requires antigen-specific interactions between Dendritic cells (DC) and naive CD8 T cells in secondary lymphoid organs. We aim to understand how the dynamic migratory behavior of myeloid and lymphoid cells is coordinated to ensure that “the right cells” communicate at “the right time” in “the right place” to enable robust immune responses. Using intravital microscopy, we have recently identified a critical phase (“Step 2”) of T cell priming that follows the initial encounter of DC and CD8 T cells and is essential to develop protective immunity.
The aim of this proposal is to identify the cellular and molecular mechanisms regulating T cell differentiation during Step 2. We will employ a newly developed imaging method (“Net-Vis”) to investigate how key elements of Step 2 (XCR1 DC) receive antigenic and inflammatory “information” within a network of myeloid cells. Next, we will test a novel model of T cell priming in which stepwise relocalization to multicellular clusters within the LN orchestrates T cell differentiation. Combining deep-tissue intravital microscopy, “Niche-seq” and novel genetic approaches, we will identify the cellular players and molecules guiding these processes and test their mechanistic implications. Finally, we will investigate the identity and mechanisms of Foxp3+ T cells that co-regulate CD8 T cell activation and differentiation during Step 2.
In summary, we will exploit an array of innovative imaging, spatiotemporal transcriptomics and genetic approaches to investigate novel fundamental aspects of CD8 T cell priming during a newly discovered distinct phase of T cell activation and differentiation. Investigating the mechanisms that guide these central steps in adaptive immunity is anticipated to reveal new avenues for the therapeutic manipulation of immune responses against infection and cancer.
Wissenschaftliches Gebiet
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Finanzierungsplan
ERC-COG - Consolidator GrantGastgebende Einrichtung
97070 Wuerzburg
Deutschland