[F31] Investigating the role of ITK in tuning CD8+ T cell TCR signaling kinetics via the negative regulator Sprouty1

Ente: National Institute of Allergy and Infectious Diseases

Scadenza: 2028-05-31

Importo max: 38.798 EUR

Paese: US

Descrizione

PROJECT SUMMARY/ABSTRACT The strength and duration of T cell receptor (TCR) signaling are critical for regulating CD8+ T cell activation, differentiation, and long-term memory potential. A deeper understanding of how TCR signaling is controlled in response to antigens of varying affinities is essential for improving T cell-based immunotherapies for human diseases and cancer. The Berg lab has previously described the role of IL-2-inducible T cell kinase (ITK) in regulating the strength of TCR signaling in response to peptides of varying affinities, by causing graded expression of effector molecules. However, our preliminary data suggests that CD8+ T cells deficient in ITK exhibit TCR signaling with a reduced overall magnitude and dysregulated termination, showing prolonged TCR signaling kinetics. Improper regulation of TCR signal termination may result in altered T cell differentiation or hyperactivity. Therefore, the goal of this proposal is to further define how ITK tunes TCR signaling in CD8+ T cells, with a focus on the termination of TCR signaling. We have identified several negative regulators of TCR signaling with significantly reduced expression in ITK-deficient CD8+ T cells, including Sprouty1. Sprouty1 has been shown to inhibit both the MAPK pathway and the phosphorylation of proximal signalosome molecules LAT and PLC-1. We propose a model where ITK induces graded expression of Sprouty1 proportional to the strength of TCR stimulation, which leads to graded termination of TCR signaling. In this proposal, we will utilize the OT-I transgenic model to stimulate CD8+ T cells with peptide antigens of high, medium, and low affinities for the OT-I TCR. In Aim 1, we will elucidate the molecular mechanisms downstream of ITK that regulate graded Sprouty1 expression. In Aim 2, we will utilize the novel Nr4a3-Tocky fluorescent reporter model, which provides temporal and quantitative information about TCR signaling. This will allow us to investigate how TCR signal termination is regulated in response to varying antigen affinities, and the roles ITK and Sprouty1 play in this process. Findings from this work will provide insight into how TCR signal termination is regulated, with important implications for the development of immunotherapies that rely on modulating TCR signaling. Our long-term goal is to identify targets downstream of ITK that would allow for the therapeutic tuning of TCR signal termination while preserving TCR signal initiation. This research will be conducted in the laboratory of Dr. Leslie Berg at the University of Colorado Anschutz Medical Campus (CU-AMC). The training plan emphasizes development in independent research and leadership, scientific communication, career development, and mentorship. CU-AMC offers a highly collaborative research environment with a wide range of immunological research focuses. There are ample opportunities to collaborate, present research updates, and gain feedback from leading experts in the field, which Istituzione: UNIVERSITY OF COLORADO DENVER PI: Zoe K Bedrosian Progetto: 1F31AI200278-01

Settori: National Institute of Allergy and Infectious Diseases

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