Evolving Concepts in the Roles of Galectins in Innate Immunity 公开
Arthur, Connie Maridith (2012)
Abstract
Abstract
Multiple facets of an effective immune response require efficient
communication between multiple immune factors. Much of this
signaling occurs through decoding the signals of distinct
carbohydrate patterns found on individual cells. Members of
the galectin family of carbohydrate binding proteins play a
significant role in this process. Indeed previous studies have
implicated galectin family members in regulation of numerous
immune functions, including immune cell turnover, immune
cell proliferation, and induction of cytokine secretion.
Additionally, several galectins have been implicated in the
regulation of leukocyte turnover. Several members of the
galectins family possess the unique ability to induce
exposure of phosphatidylserine (PS) to the surface of non-apoptotic
cells, thus allowing their clearance by macrophages,
independent of apoptosis. Crosslinking of carbohydrate
receptors by galectin family members facilitates galectin
signaling. However, previous studies focused on galectins
that crosslink receptors through oligomerization of a single
carbohydrate recognition domain (CRD). It remained unclear
however, whether tandem repeat galectin, Gal-8 which
possesses two distinct CRDs, could also function in this
role, and what effect multiple CRDs would have on the glycan
recognition and signaling by this lectin. Additionally, recent
studies have demonstrated that galectins may serve important
roles in direct recognition of microbial invaders. However,
given what is known about the preference of galectins for
self antigens, it seems unlikely that they could serve in a
traditional pattern recognition receptor (PRR) context.
However, studies have shown that several bacterial species
display self-like antigens on their surface that might serve to
shield these bacteria from recognition by immune defenses.
Given their proclivity for self antigens, galectins are
uniquely poised to provide protection against these
bacteria. As receptor-ligand interactions provide the
fundamental basis for biological activity, we first
sought to explore the carbohydrate binding specificity of Gal-4 and
Gal-8. Using obtained information regarding ligand
specificity, we asked whether and how this ligand
specificity might impact cellular signaling and specific
immunity against microbes baring self-like
antigens. Taken together, these studies provide
significant insight into the pivotal role of the galectin
family of carbohydrate binding proteins as factors of immune
protection.
Table of Contents
TABLE OF CONTENTS
Abstract Cover Page
Abstract
Cover Page
Acknowledgements
Table of Contents
List of Figures and Tables
Chapter 1: Introduction
1
Figures
10
Figure Legends
13
Chapter 2: Dimeric Galectin-8 induces phosphatidylserine
exposure in leukocytes
through polylactosamine recognition by the C-terminal
domain.
Introduction
15
Results
Gal-8 induces PS exposure in HL60 cells
17
Desialylation of HL60 Cells Does Not Alter Gal-8 Binding Yet
Enhances
Gal-8-induced PS Exposure
18
Gal-8N and Gal-8C Fail to Induce PS Exposure in HL60 Cells
20
Gal-8 Exists as a Dimer
21
Only Gal-8NM Recognizes Cell Surface polyLacNAc Glycans
22
Gal-8 Induces PS Exposure Entirely through C-terminal Domain
24
Gal-8 Recognizes Four Primary Classes of Glycans
24
Each Gal-8 CRD Binds Distinct Classes of Glycans
25
Discussion
26
Figures
32
Figure Legends
42
Chapter 3: Signaling of PS Exposure by Gal-8 Requires Presence of
Complex N-
glycans.
Introduction
47
Results
Gal-8 recognition of complex glycan structures
50
Gal-8 cell surface recognition of complex-O-glycans and
glycolipids
51
Gal-8 signals through recognition of complex-N-glycans
52
Complex N glycans significantly influence glycan recognition by
Gal-8C
53
Gal-8N inhibits Gal-8 signaling through recruitment away from
Gal-8C
signaling domains
54
Discussion
54
Figures
58
Figure Legends
62
Chapter 4: Innate Immune Lectins Kill Pathogens Expressing Blood
Group
Antigens
Introduction
64
Results
Galectins recognize blood group positive bacteria
65
Gal-4 and Gal-8 kill blood group-positive bacteria
67
Galectin killing requires blood group antigen recognition
69
Galectins specifically kill blood group positive bacteria in
vivo
71
Discussion
73
Figures
75
Figure Legends
79
Chapter 5: Microbial microarray reveals complementary defense
against potential
pathogens
Introduction
83
Results
Generation of a Microbial Glycan Microarray (MGM)
84
MGM analysis reveals distinct serological responses
84
MGM reveals potential targets for galectin-mediated immunity
86
In silico approach identifies novel targets of galectin-mediated
immunity
88
Gal-4 and Gal-8 specifically kill bacteria
90
Discussion
91
Figures
93
Figure Legends
96
Chapter 6: Galectin-7 possesses innate killing ability towards
pathogens bearing
self-like antigen
Introduction
98
Results
Gal-7 recognizes and kills blood group-positive bacteria
100
Gal-7 killing requires blood group antigen recognition
102
Gal-7 recognizes extended polymerizing O antigen preferentially
103
Gal-2 binds but does not kill blood group-positive bacteria
105
Microbial Glycan Microarray (MGM) reveals novel targets for
Gal-7-
mediated immunity
106
Discussion
107
Figures
109
Figure Legends
113
Chapter 7: Summary and Future Directions
116
Materials and Methods
127
References
137
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