Date of Award

January 2021

Document Type

Thesis

Degree Name

Medical Doctor (MD)

Department

Medicine

First Advisor

Suguru Imaeda

Second Advisor

Keith Choate

Abstract

The accumulation and adhesion of tissue-resident regulatory T cells (Tregs) to particular nichesoptimally mediate their tissue-specific functions while these Tregs are in a highly activated state. However, how Treg accumulation and activation in these tissues is regulated is incompletely understood. In preliminary research, LAYN (layilin), a C-type lectin-like receptor, was found to be highly and preferentially expressed on a subset of activated Tregs in healthy and diseased human skin using an unbiased discovery approach. Germline Layilin-/- mice and mice with layilin-deficient Tregs were generated to elucidate the function of layilin in Tregs in vivo. Our work then found that Tregs transduced for layilin overexpression in vitro showed decreased activation and suppressive ability and mice with layilin-deficient Tregs injected with MC38 cancer cells had significantly greater tumor burden as well as reduced proinflammatory immune infiltrate in tumors. This suggests that layilin attenuates Treg function. These mice also had reduced Treg infiltration in tumors which was consistent with the overexpression of layilin on Tregs promoting their accumulation in tissues during states of inflammation. In collaboration with other research groups, further experiment with intravital two-photon imaging revealed that layilin-deficient Tregs had significantly increased motility in skin which suggests layilin’s function as a Treg anchor in tissues. Hence, we identify layilin as a novel cell surface receptor which plays a major role in attenuating Treg activation and function while promoting their accumulation in tissues.

Comments

This thesis is restricted to Yale network users only. This thesis is permanently embargoed from public release.

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