Regulation of CD4 and CD8 T Cell Responses during Vaccination and Viral Infection Open Access

Abstract

To design more effective therapeutic strategies and vaccines with the aim of restoring or enhancing functional T cell responses against chronic viral infection and cancer, it is important to better understand T cell responses to vaccine vectors and how T cells can be modulated to recover their functions under persistent antigenic stimulation.

In the first part of this work, we characterize CD4 T cells elicited by Adenovirus serotype 5 (Ad5) vectors. We examined CD4 T cell responses following immunization of mice with Ad5 vectors encoding full-length lymphocytic choriomeningitis virus (LCMV)-glycoprotein (GP) compared to those induced by an acute LCMV infection. In contrast to LCMV infection where balanced CD4 T helper 1 (Th1) and T follicular helper (Tfh) responses were generated, Ad5 immunization resulted in significantly reduced Th1 differentiation. Analysis at early time points after immunization with Ad5 vectors revealed a defect in the expression of CD25 (interleukin-2[IL-2] receptor alpha chain) on Ad5-elicited CD4 T cells and administration of exogenous IL-2 following Ad5 immunization partially restored Th1 responses. These results suggest that impairment of Th1 commitment after Ad5 immunization could be due to reduced IL-2-mediated signaling.

In the second part of this work, we address how blockade of cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) and programmed cell death-1 (PD-1) affects differentiation of virus-specific CD4 and CD8 T cells in a adoptive transfer system during chronic LCMV infection. Both CTLA-4 and PD-1 are inhibitory receptors induced by T cell activation with high expression levels on exhausted T cells. Blocking these negative regulatory pathways can rescue exhausted T cells during chronic infection and cancer. Both CTLA-4 and PD-1 pathway blockade generated more virus-specific Th1 cells. However, in contrast to PD-1 pathway blockade, which had a pronounced effect in rescuing exhausted CD8 T cells in terms of both quantity and quality, CTLA-4 blockade combined with CD4 T cell transfer did not further promote LCMV-specific CD8 T cell responses or viral control compared to CD4 T cell transfer alone. Thus, our results show that individual inhibitory receptors can differentially regulate CD4 and CD8 T cell responses during chronic viral infection, with important implications for combination immunotherapy.

Table of Contents

Chapter 1: Introduction

I. CD4 T cell responses during viral infection..............................................................................................1

1. Th1 and Tfh differentiation...........................................................................................................1

2. Role of CD4 T cells during viral infection.........................................................................................4

2.1. CD4 T cell-mediated CD8 T cell help...................................................................................5

2.2. CD4 T cell-mediated B cell help..........................................................................................7

2.3. CD4 T cell-mediated direct effector functions.......................................................................8

2.4. Role of CD4 T cells during chronic viral infection...................................................................9

II. T cell exhaustion ................................................................................................................................. 12

III. T cell-based immunotherapy................................................................................................................15

1. Role of Inhibitory receptors in T cell exhaustion and therapeutic potential of manipulating inhibitorreceptor pathways........................................................................................................................................15

1.1. PD-1

The role of the PD-1 pathway in T cell exhaustion. ............................................................. ..........15

The therapeutic potential of PD-1 pathway blockade in chronic viral infection...................................17

The PD-1 pathway in antitumor immunity and PD-1-directed cancer immunotherapy........................19

1.2. CTLA-4............................................................................................................................25

1.3. Combination of inhibitory receptor blockade..........................................................................28

2. Adoptive T cell immunotherapy.......................................................................................................30

3. Combination therapy of adoptive T cell transfer and inhibitory receptor blockade...................................33

Chapter 2: Adenovirus serotype 5 vaccination results in suboptimal CD4 T helper 1 responses in mice

I. Summary.............................................................................................................................................35

II. Introduction........................................................................................................................................37

III. Results..............................................................................................................................................39

IV. Discussion..........................................................................................................................................49

V. Materials and Methods...........................................................................................................................53

Chapter 3: Differential effects of blocking PD-1 and CTLA-4 pathways in regulating virus-specific CD4

and CD8 T cells during chronic LCMV infection

I. Summary.............................................................................................................................................70

II. Introduction........................................................................................................................................72

III. Results..............................................................................................................................................76

IV. Discussion..........................................................................................................................................83

V. Materials and Methods...........................................................................................................................87

Chapter 4: Discussion

I. CD4 T cell responses following immunization with Ad5 vectors....................................................................101

II. Differential effects of blocking PD-1 and CTLA-4 pathways in regulating virus-specific CD4 and CD8 T cells

during chronic LCMV infection....................................................................................................................106

References............................................................................................................................................111

About this Dissertation

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School	Laney Graduate School
Department	Biological and Biomedical Sciences
Degree	PhD
Submission	Dissertation
Language	English
Research Field	Health Sciences, Immunology Biology, Virology
Keyword	T helper 1 cells Inhibitory receptors T follicular helper cells Chronic viral infection CD8 T cells Vaccination
Committee Chair / Thesis Advisor	Ahmed, Rafi, Emory University
Committee Members	Evavold, Brian, Emory University Speck, Sam, Emory University Jacob, Joshy, Emory University Altman, John D, Emory University

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