Antigen presenting cells and cytokines in the differentiation of effector CD8+ T cell and tissue resident CD8+ T Cell responses to influenza. Restricted; Files Only

Dunbar, Paul (Fall 2019)

Permanent URL: https://etd.library.emory.edu/concern/etds/0v838166n?locale=es
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Abstract

CD8 effector T cell responses, and in particular lung resident memory CD8 T cells (TRM) are critical for protection against respiratory viruses, but the cellular and cytokine interactions required for their development are poorly understood. Herein we describe roles for APCs and cytokines for the development of effector and tissue resident CD8 responses to influenza. Chapter 2 demonstrates the necessity of classical monocytes for the establishment of lung TRM following influenza infection. We find that, during the initial appearance of lung TRM, monocytes and dendritic cells are the most numerous influenza antigen-bearing APCs in the lung. Surprisingly, depletion of DCs after initial T cell priming did not impact lung TRM development or maintenance. In contrast, a monocyte deficient pulmonary environment in CCR2-/- mice results in significantly less lung TRM following influenza infection, despite no defect in the antiviral effector response or in the peripheral memory pool. IL-27 has pleiotropic effects on a range of immune cells, but the impact of IL-27 signaling on antigen-specific CD8 T cells responding to a respiratory viral infection has not been thoroughly studied. We utilized a direct competition model to compare antiviral CD8 T cell response in the presence and absence of IL-27 signaling following influenza infection. We find that while CD8 T cells lacking the IL-27 receptor (IL-27R) are competent to expand following stimulation in vitro, they exhibit a severe accumulation defect in both peripheral and lymphoid tissues during acute infection. Although this defect was supported by decreased proliferation in the lung and the development of fewer terminally-differentiated effector cells in the absence of IL-27 signaling, these observations could not fully account for the impaired expansion of virus-specific IL-27R-/- CD8 T cells. However, RNA-sequencing analysis of WT and IL27R-/- CD8 T cells revealed differential expression of genes involved in apoptosis. Furthermore, we observed that IL-27R-/- CD8 T cells entered apoptosis at a greater rate than their WT counterparts in both peripheral and lymphoid tissues. Together, these findings have identified novel mechanisms regulating the establishment and protective efficacy of CD8 populations. Applying these findings may aid in the development of a new vaccination strategy for enhanced CD8 T cell establishment and protection. 

Table of Contents

Chapter 1 …………………..…………………………………………………………………………. 1

Introduction: The Role of APC’s In the differentiation of Lung Tissue Resident Memory T Cells 

Table 1 …………………………………………………………………………. 5  

Figure 1 …………………………………………………………………………. 9  

Chapter 2 …………………..…………………………………………………………………………. 41

Pulmonary Monocytes Interact with Effector T Cells in the Lung Tissue to Drive TRM Differentiation Following Viral Infection 

Figure 1 …………………………………………………………………………. 66  

Figure 2 …………………………………………………………………………. 69  

Figure 3 …………………………………………………………………………. 71  

Figure 4 …………………………………………………………………………. 74  

Figure 5 …………………………………………………………………………. 76  

Figure 6 …………………………………………………………………………. 79  

Figure 7 …………………………………………………………………………. 81  

Figure 8 …………………………………………………………………………. 83  

Figure 9 …………………………………………………………………………. 88  

Figure 10 …………………………………………………………………………. 90 

Chapter 3 …………………..…………………………………………………………………………. 106

CD8 Intrinsic IL-27R signaling is Required for the Development of a Robust CD8 Effector Response Following Influenza Infection 

Figure 1 …………………………………………………………………………. 111  

Figure 2 …………………………………………………………………………. 115 

Figure 3 …………………………………………………………………………. 118  

Figure 4 …………………………………………………………………………. 120  

Figure 5 …………………………………………………………………………. 123 

Figure 6 …………………………………………………………………………. 125  

Figure 7 …………………………………………………………………………. 128  

Figure 8 …………………………………………………………………………. 130   

Chapter 4 …………………..…………………………………………………………………………. 137

Pulmonary Monocytes Interact with Effector T Cells in the Lung Tissue to Drive TRM Differentiation Following Viral Infection 

Figure 1 …………………………………………………………………………. 140 

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