Influence of Regulatory and IL-17-Secreting T Cells in the Pathogenesis of SIV Infection Open Access

Nigam, Pragati (2010)

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Pathogenic HIV/SIV infections are characterized by severe CD4+ T cell depletion, hyperimmune activation and damage to gastrointestinal tract resulting in immune dysregulation. Understanding the early events at the site of virus exposure are critical to determine immune correlates for virus control and disease progression. CD4+ regulatory cells (Tregs) may influence viral control and disease progression by suppressing anti-viral immunity. However, these cells are infected and killed very early following SIV infection. Here, we demonstrate that pathogenic SIV infections utilize a novel immunosuppressive mechanism wherein they induce rapid expansion of CD8+Tregs with suppressive capacity in colorectal tissue, one of the preferential sites of virus replication. The expansion of CD8 Tregs was not seen in non-pathogenic SIV infection of sooty mangabeys suggesting that these cells may be deleterious to the host and contribute to faster disease progression.

IL-17 is a pro-inflammatory cytokine that is important for protection against extracellular bacteria in the gut and maintenance of gut permeability. IL-17 producing CD4 T cells (Th17) have been well characterized and are depleted very early following SIV infection. It is increasingly becoming clear that a subset of CD8 T cells in humans and mice secrete IL-17 (Tc17), and the role of these cells is yet to be characterized for any infectious disease including HIV/SIV. Here we demonstrate that, in contrast to Th17 cells, the Tc17 cells are not depleted during the acute phase of infection, however are depleted during the end stage disease. We also demonstrate that Tc17 cells are not depleted in SIV-infected sooty mangabeys. These results suggest that Tc17 cells may compensate for the loss of Th17 cells during the acute and early chronic phases of pathogenic SIV infection and may play a role in prolonging disease progression.

In conclusion, our findings reveal important roles for gut resident CD8 Tregs and Tc17 cells in regulating SIV disease progression. Whereas CD8+ Tregs help the virus by constraining anti-viral immunity, Tc17 cells delay onset of disease by contributing to the maintenance of intestinal epithelial barrier.

Table of Contents

Table of contenTS

Chapter 1: Page


Introduction to HIV 1

Lineage differentiation of T cells 11

Regulatory T cell 15

Regulatory T cells during the course of HIV/SIV infections 20

Th17 and Tc17 T cells 23

Th17 and Tc17 cells during HIV/SIV infections 27

Interplay between regulatory T cells and Th17 T cells 30

Chapter 2:

Expansion of FOXP3+ CD8 T cells with suppressive potential in colorectal mucosa following a pathogenic SIV infection correlates with diminished anti-viral T cell response and viral control

Abstract 34

Introduction 35

Materials and Methods 38

Results 44

Discussion 54

Legends to the figures 59

Figures 64

Chapter 3:

Loss of IL-17 producing CD8 T cells during late chronic stage of pathogenic SIV infection is associated with disease progression

Abstract 73

Introduction 74

Materials and Methods 76

Results 80

Discussion 88

Legends to the figures 91

Figures 94

Chapter 4:

Discussion 102

References 112


(listed in order of appearance)

Chapter 1: Page

Figure 1.1 T cell differentiation 13

Figure 1.2 FOXP3 gene 17

Chapter 2:

Figure 2.1 FOXP3 positive T cells in normal rhesus macaques 64

Figure 2.2 Expansion of CD8+FOXP3+ T cells post SIV infection in rhesus

macaques 65

Figure 2.3 Expansion of CD8+ Tregs in various tissues of normal and SIV-

infected rhesus macaques 66

Figure 2.4 Characterization of CD8+ Tregs 67

Figure 2.5 Suppressive potential of CD8+ Tregs in vitro 68

Figure 2.6 Association between CD8+ Tregs with anti-viral T cell response in

SIV-infected rhesus macaques in vivo 69

Figure 2.7 Relationship between CD8+ Tregs and CD4+ Tregs with viral load in

SIV-infected macaques, and effect of ART on regulatory T cells 70

Figure 2.8 CD8+ Tregs in Sooty mangabeys 71

Chapter 3:

Figure 3.1 Distribution of T cell subsets in normal rhesus macaques 95

Figure 3.2 Polyfunctionality of T cell subsets 96

Figure 3.3 Characterization of T cell subsets 97

Figure 3.4 Kinetics of CD8+ T cell subsets after pathogenic SIV infection 98

Figure 3.5 Kinetics of CD4+ T cell subsets after pathogenic SIV infection 99

Figure 3.6 Characterization of T cell subsets post SIV infection 100

Figure 3.7 Effect of ART on T cell subsets 101

Figure 3.8 Comparison of T cell subset levels in Sooty mangabeys 102

Chapter 4:

Figure 4.1 Proposed model of events during SIV infection 105

Figure 4.2 Timeline of events during the course of SIV infection 105


(listed in order of appearance)

Chapter 1: Page

Table 1 Features of pathogenic and non-pathogenic SIV infections 5

Table 2 T cell subset functions 12

Table 3 Regulatory T cell subsets 16

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