All ETDs from UAB

Advisory Committee Chair

Louis B Justement

Advisory Committee Members

Peter D Burrows

Claude H Steele

Janusz Kabarowski

Randall S Davis

Document Type

Dissertation

Date of Award

2013

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

Acute inflammation is a necessary component for the clearance of pathogens. Cells at the site of infection utilize highly conserved receptors to both recognize microbes and induce the production of pro-inflammatory stimuli. These stimuli set off a chain reaction that includes localized vasodilation, leukocyte infiltration, and tissue destruction, collectively known as inflammation. Tightly controlled, this process is protective, and can compartmentalize the damage to a defined area, but when dysregulated can be catastrophic, inducing chronic inflammation and even death. Families of innate receptors can modulate inflammatory processes, and in doing so, increase or decrease their severity, as well as tailor responses to various infections. Of note, proteins of the immunoglobulin super family (IgSF) are a large, well characterized group of receptors that regulate processes such as cell adhesion, migration, signaling, and phagocytosis. Recently, a subclass of IgSF proteins, the Triggering Receptor Expressed on Myeloid cells, or TREM, family of proteins has emerged as a group of receptors involved in modulating cellular responses during inflammation. Of the genes in the TREM locus, four have conserved protein products; TREM-1, TREM-2, Trem-like transcript 1 (TLT1), and Trem-like transcript 2 (TLT2). Study of the biology of these receptors has revealed that members of the TREM family are capable of modulating a variety of immune cell functions. TREM-1 amplifies the immune response to bacterial stimuli by increasing leukocyte production of pro-inflammatory cytokines, as well as enhancing leukocyte/platelet interactions. TREM-2 is important for dampening inflammatory signals in the central nervous system and in maintaining homeostasis during bone resorption. TLT1 plays a role in augmenting platelet aggregation as well as leukocyte interactions. Less is known concerning the role TLT2 plays during inflammation. Here, we describe that TLT2 expression is conserved between mouse and man, and is the only TREM member distributed on cells of both the myeloid and lymphoid lineage. This pattern of expression is modulated by inflammatory stimuli, a preserved feature of the TREM family. Specifically, TLT2 is found intracellularly in neutrophils, and is rapidly translocated to the cell surface upon degranulation. These observations add to the growing biology of TLT2, and will be useful in further elucidating its role during immune responses.

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