Coinhibitory Receptor Control of T Cell Responses in Transplantation Público
Laurie, Sonia (Summer 2018)
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 CD28null 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-1lo CD127hi 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
About this Dissertation
School | |
---|---|
Department | |
Subfield / Discipline | |
Degree | |
Submission | |
Language |
|
Research Field | |
Palavra-chave | |
Committee Chair / Thesis Advisor | |
Committee Members |
Primary PDF
Thumbnail | Title | Date Uploaded | Actions |
---|---|---|---|
Coinhibitory Receptor Control of T Cell Responses in Transplantation () | 2018-07-23 13:30:26 -0400 |
|
Supplemental Files
Thumbnail | Title | Date Uploaded | Actions |
---|