IL-27 REGULATES TIGIT ON MEMORY T CELLS DURING SEPSIS Public
Morrow, Kristen (Fall 2020)
Published
Abstract
Sepsis is a leading cause of morbidity and mortality worldwide. While most patients survive the first 30 days, long-term mortality is high due to immunosuppression. This immunosuppression is linked to heightened levels of immunoregulatory cytokines. The cytokine IL-27 is of particular interest, as it induces the co-inhibitory molecules TIGIT and PD-1 on CD4+ and CD8+ T cells during cancer and chronic viral infection. IL-27 is also linked to mortality in mouse models of sepsis. Therefore, our work examined IL-27’s impact on T cells, particularly memory T cells, which prevent secondary infections after sepsis. We used the murine model of cecal ligation and puncture (CLP) to model sepsis induced by ruptured appendicitis in humans.
We found that most T cells express the IL-27 receptor (IL-27Rɑ) following CLP. However, memory T cells expressing IL-27Rɑ are significantly reduced in number and frequency compared to naïve T cells. Further analysis revealed that IL-27Rɑ associates with TIGIT expression on memory CD4+, but not CD8+, T cells during sepsis. Surprisingly, IL-27 was not associated with PD-1 expression in either T cell population. The induction of TIGIT was not associated with alterations in cellular apoptosis and was instead associated with increased proliferation of IL-27Rɑ+ T cells one day following CLP.
Although IL-27 was previously reported to regulate TIGIT on FoxP3+ regulatory T cells, the frequency of regulatory T cells was unaltered by IL-27 signaling. While TIGIT expression was not associated with alterations in IFN𝛾 production, memory CD4+ T cells expressing TIGIT had a reduced capacity to produce TNF. Ultimately, the IL-27 induced differences in memory T cells were not associated with changes in sepsis mortality – genetic abrogation of IL-27 signaling and blockade of IL-27 did not lead to any improvements.
These findings suggest that the induction of co-inhibitory molecules by IL-27 is disease-state and context-dependent. Further studies are needed to determine the factors that regulate IL-27’s function during sepsis compared to other disease states.
Table of Contents
TABLE OF CONTENTS.. i
LIST OF FIGURES.. iii
CHAPTER 1: INTRODUCTION.. 1
I. AN OVERVIEW OF SEPSIS. 1
Treating sepsis 3
Early clinical trials for sepsis. 4
Recent clinical trials for sepsis. 6
Modeling sepsis in mice. 7
II. THE DYSFUNCTIONAL IMMUNE RESPONSE TO SEPSIS.. 8
Innate immune response to sepsis 9
Adaptive immune response to sepsis. 11
The cytokine response to sepsis 14
III. IL-27 AND SEPSIS. 16
The role of IL-27 in sepsis pathophysiology 17
Interactions between IL-27 and other cytokines relevant to sepsis 18
IL-27 and IL-17. 19
IL-27 and IL-33. 20
IV. IL-27 AND T CELL FUNCTION.. 21
IL-27 and Treg. 21
IL-27 and memory T cells 22
IL-27 and co-inhibitory markers. 22
V. FIGURES. 24
CHAPTER 2: THE IL-27 RECEPTOR REGULATES TIGIT ON MEMORY CD4+ T CELLS DURING SEPSIS 26
I. ABSTRACT. 26
II. INTRODUCTION.. 26
III. METHODS. 29
IV. RESULTS. 33
V. DISCUSSION.. 40
VI. FIGURES. 48
CHAPTER 3: CONCLUSION.. 65
References 75
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