Interplay between T and B cell responses during chronic viralinfection Öffentlichkeit

Abstract

The adaptive immune response has evolved multiple mechanisms for protection against invading pathogens. CD8 T cells mediate protection against intracellular pathogens by killing infected cells, whereas the B cell response provides antibody that can neutralize foreign pathogens. Additionally, CD4 T cell responses are important for activating CD8 T cell and B cell responses. Although the importance of CD4 T cells in initiating B cell responses is well established, less is understood about how CD4 T cells initiate or sustain CD8 T cell responses. This question becomes increasingly important as we try to understand why CD8 T cell responses fail during chronic viral infections such as HIV, HBV and HCV. In these infections, a poor CD4 T cell response is often associated with functional exhaustion of the CD8 T cells. To better understand the interplay between CD4 T cell responses and CD8 T cell exhaustion, we examined the effects of altering CD4 T cell and B cell responses during chronic LCMV infection of mice. We first examined the question of how transient removal of CD4 T cell help affects long-term CD8 T cell responses. Secondly, we determined whether improving CD4 T cell help would affect CD8 T cell exhaustion. A transient one-week blockade of CD4 T cell help via administration of αCD40L blocking antibody beginning at two weeks post infection had no direct effect on the function of CD8 T cells but resulted in reduced CD4 T cell function and decreased levels of humoral immunity. This decreased CD4 T cell response then resulted in greater CD8 T cell exhaustion and impaired viral clearance. On the other hand, adoptive transfer of virus specific CD4 T cells during chronic LCMV infection restored function in exhausted CD8 T cells and also enhanced antibody responses. This rescue was observed for several CD8 T cell epitopes, was synergized by αPD-L1 treatment, and resulted in improved viral control in treated animals. Thus, these studies provide insights into how CD4 T cells and B cells can affect CD8 T cell programming and how one might design therapies to combat chronic infections in humans.

Table of Contents

Table of Contents

Table of Contents List of Figures Table of Contents Chapter 1: Introduction Part I: Regulation of Immune Responses during acute and chronic infections...........2 Part II: Humoral Immunity: Germinal centers, long-lived plasma cells and memory B cells.....................................................................................14 Chapter 2: Transient CD40:CD154 blockade inhibits B cell responses and prevents viral control during chronic LCMV infection Abstract.............................................................................................27 Introduction.........................................................................................28 Materials and Methods............................................................................32 Results...............................................................................................37 Discussion..........................................................................................45 Figure Legends.....................................................................................49 Chapter 3: CD4 T cell help rescues exhausted CD8 T cells Abstract..............................................................................................59 Introduction..........................................................................................60 Materials and Methods.............................................................................62 Results.................................................................................................66 Discussion...........................................................................................73 Figure Legends......................................................................................78 Chapter 4: Tracking human antigen-specific memory B cells: a sensitive and generalized ELISPOT system Abstract..............................................................................................91 Introduction..........................................................................................91 Materials and Methods..............................................................................93 Results................................................................................................95 Discussion..........................................................................................100 References...........................................................................................101 Supplemental Figure Legend.....................................................................103 Chapter 5: Discussion and Future Directions.............................................107 References..........................................................................................114

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School	Laney Graduate School
Department	Biological and Biomedical Sciences
Degree	PhD
Submission	Dissertation
Language	English
Research Field	Health Sciences, Immunology
Stichwort	chronic viral infection CD4 T cells memory B cell LCMV CD8 T cell exhaustion humoral immunity
Committee Chair / Thesis Advisor	Ahmed, Rafi, Emory University
Committee Members	Lukacher, Aron E, Emory University Larsen, Christian P, Emory University Williams, Ifor R, Emory University Amara, Rama Rao, Emory University

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