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PHONG, BINH L (2016) REGULATION OF MAST CELL FUNCTION BY TIM-1 AND TIM-3 SIGNALING. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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The T cell (or transmembrane) immunoglobulin and mucin domain (TIM) family proteins have attracted significant attention as novel immune regulators. Tim-3 is expressed on chronically stimulated, often dysfunctional, T cells. Antibodies to Tim-3 can enhance anti-viral and anti-tumor immune responses. It is also constitutively expressed by mast cells, NK cells and specific subsets of macrophages and dendritic cells. There is ample evidence for a positive role for Tim-3 in these latter cell types, which is at odds with the model of Tim-3 as an inhibitory molecule on T cells. On the other hand, polymorphisms in the TIM-1 gene, particularly in the mucin domain, have been associated with atopy and allergic diseases in mice and human. Genetic- and antibody-mediated studies revealed that Tim-1 functions as a positive regulator of Th2 responses, while certain antibodies to Tim-1 can exacerbate or reduce allergic lung inflammation. Tim-1 can also positively regulate the function of B cells, NKT cells, dendritic cells and mast cells. At this point, little is known about the molecular mechanisms by which Tim-1 and Tim-3 regulate the function of T cells or other cell types.

We have focused on defining the effects of Tim-1 and Tim-3 ligation on mast cell activation, since these cells constitutively express both proteins and are activated through an ITAM-containing receptor for IgE (FcRI), using signaling pathways analogous to those in T cells. Employing a variety of gain- and loss-of-function approaches, we find that Tim-3 acts at a receptor-proximal point to enhance Lyn kinase-dependent signaling pathways that modulate both immediate-phase degranulation and late-phase cytokine production downstream of FcRI ligation. Using a Tim-1 mouse model lacking the mucin domain (Tim-1mucin), we show for the first time that the polymorphic Tim-1 mucin region is dispensable for normal mast cell activation. We further show that Tim-4 cross-linking of Tim-1 enhances select signaling pathways downstream of FcRI in mast cells, including mTOR-dependent signaling, leading to increased cytokine production but without affecting degranulation. Thus, Tim-1 and Tim-3 are promising targets in development of therapeutics against mast cell-mediated allergic and autoimmune diseases.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
PHONG, BINH Lblp37@pitt.eduBLP370000-0003-4888-6704
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairKane, Larrylkane@pitt.eduLKANE0000-0001-5198-516X
Committee MemberGaffen, Sarah Lsarah.gaffen@pitt.eduSIG65
Committee MemberLu, Binfengbinfeng@pitt.eduBINFENG
Committee MemberLarregina, Adriana Tadrianal@pitt.eduADRIANAL
Committee MemberWenzel, Sally
Date: 20 May 2016
Date Type: Publication
Defense Date: 5 February 2016
Approval Date: 20 May 2016
Submission Date: 15 April 2016
Access Restriction: No restriction; Release the ETD for access worldwide immediately.
Number of Pages: 230
Institution: University of Pittsburgh
Schools and Programs: School of Medicine > Immunology
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: TIM-1, TIM-3, mast cells
Date Deposited: 20 May 2016 15:17
Last Modified: 15 Nov 2016 14:32


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