IL-27 REGULATES TIGIT ON MEMORY T CELLS DURING SEPSIS Open Access

Morrow, Kristen (Fall 2020)

Permanent URL: https://etd.library.emory.edu/concern/etds/3n204042t?locale=en
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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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