Date of Award

2017

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Graduate Group

Cell & Molecular Biology

First Advisor

Phillip Scott

Abstract

Cutaneous leishmaniasis is a disease characterized by highly inflammatory, sometimes disfiguring lesions that nonetheless spontaneously resolve, resulting in robust protection against reinfection. It has been known for decades that a type 1 CD4+ T cell response is critical for both primary parasite control and subsequent protection against reinfection. However, all attempts to artificially reproduce this response have failed, suggesting there may be a gap in our understanding of the memory CD4+ T cells generated by natural infection. In this work, we use a healing mouse model of cutaneous leishmaniasis to explore the role of skin-associated CD4+ T cells in this disease. We demonstrate for the first time that tissue-resident memory (TRM) CD4+ T cells are generated by leishmania infection, are long-lived, and are distributed throughout the skin. We next investigate whether or not these cells contribute to immune protection, and find that leishmania-specific TRM cells can guide the rapid recruitment of circulating T effector cells to the site of challenge, enhancing control of infection. We go on to identify another, novel mechanism of TRM cell-driven protection, in which leishmania-specific TRM cells orchestrate the rapid infiltration and activation of inflammatory monocytes, leading to robust early control of disease even in the absence of circulating T cells. Finally, we explore the requirements for the establishment of TRM cell populations in cutaneous leishmaniasis, with the ultimate goal of understanding how to harness these cells in a potential vaccine.

Available for download on Saturday, August 15, 2020

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