Date of Award

Spring 5-6-2017

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Programs

Genetics, Cell Biology & Anatomy

First Advisor

Hamid Band

Abstract

T-cells use the endocytic pathway for key cell biological functions, including receptor turn-over and maintenance of the immunological synapse. Some of the established players include the Rab GTPases, SNARE complex proteins, and others which in non-T-cell systems function together with Eps15 Homology Domain-containing (EHD) proteins. To date, the role of the EHD protein family in T-cell function remains unexplored. We generated conditional EHD1/3/4 knockout mice using CD4-Cre and crossed these with mice bearing a myelin oligodendrocyte glycoprotein (MOG)-specific TCR transgene. We found that CD4+ T-cells from these mice exhibited a reduced antigen-driven cell proliferation and IL-2 secretion in vitro. In vivo, these mice exhibited reduced severity of experimental autoimmune encephalomyelitis. Further analyses showed that recycling of the TCR-CD3 complex was impaired, leading to increased lysosomal targeting and reduced surface levels on CD4+ T-cells of EHD1/3/4 knockout mice. Our studies reveal a novel role of the EHD family of endocytic recycling regulatory proteins in TCR-mediated T-cell functions.

Fany Iseka, Permission for using Figure 1.1 Pathways of endocytosis.pdf (102 kB)
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Fany Iseka, Permission for using Figure 1.2 Architecture of EH domain-containing proteins.pdf (166 kB)
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Fany Iseka, Permission for using Figure 1.3 The structure of EHD proteins.pdf (102 kB)
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Fany Iseka, Permission for using Figure 1.5 Endocytic trafficking of signalling receptor.pdf (102 kB)
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Fany Iseka, Permission for using Figure 1.6 Later stages of the IS in T cells.pdf (230 kB)
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img106.jpg (723 kB)
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Available for download on Tuesday, October 24, 2017

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