Coinhibitory Receptor Control of T Cell Responses in Transplantation Público

Abstract

T lymphocytes are known to be key players in the cellular rejection of allografted tissue following solid organ transplantation. Immunotherapeutic strategies to prevent rejection following transplantation frequently involve targeted blockade of T cell costimulatory pathways.  We propose that in addition to costimulation blockade, harnessing the power of coinhibitory molecules that are selectively upregulated on memory-like cells will be critical to controlling donor-specific immune responses. 

Here we have performed a series of studies to assess the contribution of coinhibitory receptors to the control of alloreactive T cell responses following transplantation in humans and animal models. We demonstrate that the T cell coinhibitory molecules 2B4 and TIGIT are expressed on CD28null effector memory CD4+ and CD8+ T cells that are associated with freedom from rejection following renal transplantation in humans.  Further exploration of these pathways indicates that while 2B4 functions to control alloreactive T cells by limiting their glycolytic metabolism, and subsequently proliferation and recruitment into the alloreactive anti-donor response, antibody-mediated agonism of TIGIT signaling prolongs graft survival in a mouse model of skin transplantation.

Finally, we show programming of antigen specific CD8⁺ T cells responding to graft and pathogen are dissimilar, and that antigen-specific CD8⁺ T cells primed by a skin graft contract faster than those primed by infection, yet are able to expand more rapidly upon rechallenge.  Additionally, the expression of CD127 at a memory time point suggests graft-elicited CD8⁺ antigen specific T cells are maintained in a less terminally-differentiated state compared to gHV-elicited CD8⁺ antigen specific T cells, despite fewer cells being present at that time point.

Taken together, the data presented here suggest that the surface marker expression, metabolic prolife, and functional capacity of T cells depends on the priming conditions and may be used to predict immunologic risk following transplantation.

Table of Contents

Cover Pages …………………....……….………………..………………….…...…… p. 1

Abstract …………………....…….……………………………………..………...…… p. 4

Acknowledgements …………....……….…………..……..……………………...…… p. 5

Table of Contents …………………....……….…………..……...……………...…..… p. 6

Chapter 1. Introduction

Transplantation is a life-saving therapy for end-stage organ disease ………...……… p. 9

Characterizing Innate & Adaptive Alloimmune Responses After Solid Organ Transplantation...…… p. 11

T Cell Function is Tightly Regulated by a Balance of Costimulatory and Coinhibitory Signals………p. 24

Metabolism & Bioenergetics Impact T Cell Phenotype, Function and Fate …..…..... p. 40

T Cells and Costimulation Blockade in Transplant Tolerance, Graft Acceptance, and Alloaggression… p. 42

Conclusions………………………....……….………………………………...…...… p. 47

Figure Legends …………………....……………………..…………………………... p. 48

Figure Key ..…...……………...………………...……….……………………...…… p. 49

References ……………………………………...……….…………………………… p. 51

Figure 1.1.....…...……………...………………...……….…………………...……… p. 63

Figure 1.2.....…...……………...………………...……….…………………...……… p. 64

Chapter 2. 2B4 is a Functional Coinhibitor of Human T Cells Expressed on CD28^null TEM Cells Associated with Stability Following Renal Transplantation

Abstract ………………………………………………….……………………...…… p. 66

Introduction ………………………………………………..………………….……... p. 68

Materials and Methods ……………………………………...………………...…...… p. 71

Results ……………………………………………………….…………………….… p. 74

Discussion……………………….…………………………….…………………...… p. 78

Figures…..…………………………………………………………………….……… p. 81

Figure Legends …..…………………………………………………………...……… p. 82

References ……………………………………………………….……………...…… p. 84

Figure 2.1 ……………………………………………………………………………. p. 86

Figure 2.2 ……………………………………………………………………………. p. 87

Figure 2.3 ……………………………………………………………………………. p. 88

Figure 2.4 ……………………………………………………………………………. p. 89

Figure 2.5 ……………………………………………………………………………. p. 90

Table 2.1 ………………………………………………………………….…………. p. 91

Table 2.2 ………………………………………………………………….…………. p. 92 

Chapter 3. 2B4 Mediates Inhibition of CD8⁺ T Cell Responses via Attenuation of Glycolysis and Cell Division

Cover ………………………………………………........................................... p. 93

Abstract ………………………………………………….…………………...……… p. 94

Introduction ………………………………………………..……………….…...…… p. 95

Materials and Methods ……………………………………...………………..……… p. 98

Results ……………………………………………………….…………………...… p. 106

Discussion……………………….…………………………….………….………… p. 115

Figure Legends …..…………………………………………………….…………… p. 119

References ……………………………………………………….…………….…… p. 124

Figure 3.1……………………………………………………….…………………… p.127

Figure 3.2……………………………………………………….…………………… p.128

Figure 3.3……………………………………………………….…………………… p.129

Figure 3.4……………………………………………………….…………………… p.130

Figure 3.5……………………………………………………….…………………… p.131

Figure 3.6……………………………………………………….…………………… p.132

Figure 3.7……………………………………………………….…………………… p.133

Chapter 4. The balance of CD28 and CTLA4 signals controls TIGIT expression on

antigen-specific CD4⁺ effector T cells

Cover …………………………………………………….………………………… p. 134

Abstract ………………………………………………….………………………… p. 135

Introduction ………………………………………………..……………….……… p. 136

Materials and Methods ……………………………………...……………...……… p. 138

Results ……………………………………………………….…………………..… p. 141

Discussion……………………….…………………………….…………………… p. 143

Figures …..………………………………………………………………………… p. 145

Figure Legends …..……………………………………….………………….…… p. 146

References ………………………………………………………………………… p. 148

Figure 4.1……………………………………………………….……………….… p. 149

Figure 4.2……………………………………………………….…………….…… p. 150

Figure 4.3……………………………………………………….………….……… p. 151

Figure 4.4……………………………………………………….……………….… p. 152

Figure 4.5……………………………………………………….………..….…..… p. 153

Chapter 5. Transplantation Preferentially Induces a KLRG-1^lo CD127^hi Differentiation Program in Antigen-Specific CD8⁺ T Cells

Cover…….……………………………………………….………………………… p. 155

Abstract ………………………………………………….………………………… p. 156

Introduction ………………………………………………..………………….…… p. 157

Materials and Methods ……………………………………...………………...…… p. 159

Results ……………………………………………………….…………………..… p. 162

Discussion……………………….…………………………….…………………… p. 167

Figure Legends …..…………………………………………………….…………… p. 169

References ……………………………………………………….………….……… p. 172

Figure 5.1…..…………………………………………………….………….……… p. 174

Figure 5.1…..…………………………………………………….……….………… p. 176

Figure 5.1…..……………………………………………...……….……..………… p. 177

Figure 5.1…..…………………………………………………….……………….… p. 178

Figure 5.1…..………………………………………………………......…………… p. 179

Chapter 6. Discussion

Cover. ….…………………………………...…………….……………........……… p. 180

Coinhibitory Receptors on Antigen-experienced Memory T Cells Represent a New Class of Therapeutic Targets to Control T Cells Following Transplantation .…………..... p. 181

Conclusions and Perspectives ……………..…………….……………….....……… p. 185

References ……………………………………...……….………………….….…… p. 189

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School	Laney Graduate School
Department	Biological and Biomedical Sciences
Subfield / Discipline	Immunology and Molecular Pathogenesis
Degree	Ph.D.
Submission	Dissertation
Language	English
Research Field	Health Sciences, Immunology
Palavra-chave	Transplantation, T lymphocytes, coinhibitory receptors
Committee Chair / Thesis Advisor	Ford, Mandy, Emory University
Committee Members	Jacob, Joshy, Emory University Iwakoshi, Neal, Emory University Tirouvanziam, Rabindra, Emory University Evavold, Brian,

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