Role of FcγRIIB as a Cell-Autonomous Coinhibitor that Limits Effector CD8+ T Cell Immunity Restricted; Files Only

Abstract

Transplantation is a life-saving therapy for many individuals with end-stage organ failure. However, recipient CD8⁺ T cells are a barrier to long-term graft outcomes due to their ability to respond and reject the transplanted organ. Current immunosuppressive strategies to prevent organ rejection are associated with many drug-induced morbidities. A costimulation blockade therapeutic, belatacept, which is a CTLA-4Ig fusion protein, specifically prevents T cell activation and limits drug-induced morbidities; however, its use is associated with increased rates of acute rejection episodes. These episodes are thought to be due to previously activated CD8⁺ T cells that evade the requirements for costimulation. Our studies aimed to understand if CD8⁺ T cells utilize other molecules that can be therapeutically targeted in addition to costimulatory signals.

Here, we find that FcγRIIB, an inhibitory Fc receptor, is expressed by previously activated CD8⁺ T cells. We define a cell-autonomous function of CD8⁺ T cell-expressed FcγRIIB in limiting effector CD8⁺ T cells by inducing apoptosis through caspase 3/7 activation. This phenomenon was not transplant-specific, as antigen-specific CD8⁺ T cells that lacked Fcgr2b in models of skin transplantation, cancer, and infection all resulted in enhanced CD8⁺ T cell responses. Unexpectedly, ligation with the immunosuppressive cytokine Fgl2, not antibodies, induced this apoptotic signature in FcγRIIB⁺ CD8⁺ T cells. Data in human transplant patients indicated that FCGR2B mRNA associates with freedom from rejection in kidney transplant patients that undergo tacrolimus withdrawal, indicating its potential clinical significance in transplantation.

In addition to these findings, we found a distinct difference in FcγRIIB expression on CD8⁺ T cells following infection with pathogens that were acutely cleared, maintained latency, or established chronic infection. CD8⁺ T cells stimulated with a chronic pathogen were unable to express FcγRIIB and more rapidly elicited graft rejection. Studies revealed that in the chronic environment, there were significantly higher Fgl2 plasma concentrations and a preferential loss of memory FcγRIIB⁺ CD8⁺ T cells.

These findings identify FcγRIIB-Fgl2 as a novel CD8⁺ T cell pathway that has implications in the fields of transplantation, cancer, and infectious disease. Further elucidation of the utility of this pathway in modulating CD8⁺ T cell responses is needed. 

Table of Contents

Table of Contents

Chapter 1

History of Transplantation...................................................................................... 2

T Cells as Mediators of Organ Rejection................................................................. 4

Immunosuppressive Strategies to Prevent Organ Rejection..................................... 6

Targeting Costimulatory Molecules to Prevent Organ Rejection............................. 8

Targeting Coinhibitory Molecules to Prevent Organ Rejection.............................. 15

Fcγ Receptors........................................................................................................ 22

Premise of Research............................................................................................... 31

References............................................................................................................. 33

 

Chapter 2

Abstract................................................................................................................ 52

Introduction.......................................................................................................... 53

Materials and Methods........................................................................................... 55

Results................................................................................................................... 66

Discussion............................................................................................................. 78

Figures and Figure Legends................................................................................... 83

Supplemental Figure and Figure Legends............................................................... 96

References............................................................................................................ 101

 

Chapter 3

Abstract.............................................................................................................. 106

Introduction......................................................................................................... 107

Materials and Methods.......................................................................................... 110

Results.................................................................................................................. 114

Discussion............................................................................................................ 119

Figures and Figure Legends.................................................................................. 123

Supplemental Figure and Figure Legends............................................................. 130

References............................................................................................................ 133

 

Chapter 4

Abstract.............................................................................................................. 137

Introduction......................................................................................................... 138

Materials and Methods.......................................................................................... 139

Results.................................................................................................................. 142

Discussion............................................................................................................ 146

Figures and Figure Legends.................................................................................. 149

References............................................................................................................ 156

 

Chapter 5

Discussion............................................................................................................ 159

References............................................................................................................ 169

About this Dissertation

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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	Biology, Cell
Palavra-chave	memory transplant FcγRIIB T cells cancer immunology
Committee Chair / Thesis Advisor	Mandy Ford, Emory University
Committee Members	Periasamy Selvaraj, Emory University Joshy Jacob, Emory University Jeremy Boss, Emory University Jacob Kohlmeier, Emory University

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