Caspase-8 Shapes the Patterns of Antiviral Cd8 T Cell and Natural Killer Cell Responses Restricted; Files Only

Feng, Yanjun (Spring 2019)

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An optimal lymphocyte response against virus infection is dictated by a delicate balance between cell proliferation and death. Infection triggers lymphocytes to undergo a dramatic proliferation resulting in an exponential accumulation. This process must be tightly regulated to prevent immunoproliferative diseases. As the central mediator of extrinsic death, caspase-8 (Casp8) can initiate apoptosis, suppress necroptosis, and regulate death-independent signaling transduction. Understanding of Casp8 function in lymphocyte activation was confounded by an unleashing of RIPK3-mediated necroptosis in the absence of Casp8. Casp8–/–Ripk3–/– (DKO) mice that lack this dysregulation open the way to study Casp8 function in lymphocytes. In this dissertation, murine cytomegalovirus (MCMV) is utilized to trigger a natural and robust adaptive Ly49H+ natural killer (NK) and T cell responses. I describe my work evaluating the role of Casp8 in the generation of antiviral immunity, and demonstrate an unexpected death-independent function of Casp8 in suppressing NK and CD8 T cell expansion.

DKO mice are immunocompetent and capable of controlling MCMV infection; however, detailed characterizations of innate and adaptive immune responses have not been reported. I found that Casp8 and RIPK3 signaling is dispensable for the generation of antiviral immunity against MCMV. Enhanced NK and T cell expansion indicates that Casp8 normally dampens the accumulation of these cells during the acute phase of MCMV infection.

Elimination of Casp8 (together with RIPK3) leads to virus-specific CD8 T cell hyperaccumulation. I found that this is due to an increase in proliferation due to Casp8-deficiency in T cells independent of environmental cues in DKO mice following infection. Notably, the Ly49H+ NK cell response drives this hyperaccumulation by promoting the T cell survival. This study highlights an antiviral natural killer cell function that promotes effector T cell expansion unless kept in check by T cell-autonomous Casp8 function.

The function of Casp8 in NK cell regulation beyond suppressing necroptosis remains unknown. I found that Casp8 has a Ly49H+ NK cell-autonomous function in restricting expansion. Strikingly, NK cell responses are ablated once RIPK1 is eliminated along with Casp8 and RIPK3. Thus, Casp8 and RIPK1 dictate the magnitude of this NK cell subset following MCMV infection. 

Table of Contents

Abstract…... iv

Acknowledgments. vi

Table of Contents. vii

List of Figures. ix

Abbreviations. x

Chapter 1: Introduction. 1

1.1         T cell responses following MCMV infection. 1

1.1.1   Priming MCMV-specific CD8 T cell responses 1

1.1.2   Features of MCMV-specific CD8 T cell responses 3

1.1.3   CD4 T cell responses following MCMV infection. 10

1.1.4   Tissue-resident CD8 T cells following MCMV infection. 11

1.2         NK cell responses following MCMV infection. 13

1.2.1   NK cell activation is determined by the balance between activating and inhibitory receptor signals 13

1.2.2   Adaptive immune features of NK cells 15

1.3         Cell death pathways 18

1.3.1   Intrinsic cell death pathway. 18

1.3.2   Extrinsic apoptotic pathway. 18

1.3.3   Necroptosis 20

1.3.4   Extrinsic cell death and host defense. 23

1.3.5   Death-independent function of Casp8. 23

1.4         Casp8 and extrinsic death pathway in the regulation of T cells and NK cells 25

1.4.1   Intrinsic death regulates T cell and NK cell during homeostasis and infection. 26

1.4.2   Casp8 and extrinsic death pathway in the regulation of T cell homeostasis. 27

1.4.3   Casp8 and extrinsic death pathway in the regulation of virus-specific T cell responses. 29

1.4.4   Casp8 and extrinsic death pathway in proliferation. 31

1.5         Figures and Figure Legends. 34

Chapter 2: Remarkably Robust Antiviral Immune Response Despite Combined Deficiency in Caspase-8 and RIPK3. ……37

2.1         Abstract 38

2.2         Introduction. 39

2.3         Results 43

2.4         Discussion. 52

2.5         Materials and Methods 57

2.6         Figures and Figure Legends 62

Chapter 3: Caspase-8 Restricts Natural Killer Cell-triggered Antiviral CD8 T Cell Hyperaccumulation 73

3.1         Abstract 74

3.2         Introduction. 75

3.3         Results 79

3.4         Discussion. 89

3.5         Materials and Methods: 95

3.6         Figures and Figures Legends 99

Chapter 4: Caspase-8 Restricts Ly49H+ NK cell expansion following Murine Cytomegalovirus Infection 113

4.1         Abstract 114

4.2         Introduction. 115

4.3         Results 118

4.4         Discussion. 123

4.5         Materials and Methods 126

4.6         Figures and Figure Legends 128

Chapter 5: Discussion and future directions. 137

References: 151

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