PHONG, BINH L
(2016)
REGULATION OF MAST CELL FUNCTION BY TIM-1 AND TIM-3 SIGNALING.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
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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Details
| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
|
| ETD Committee: |
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| 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 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/27700 |
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