B1-derived, long-lived IgM plasma cells persist in the spleen and confer long-term protection 公开

Bohannon, Caitlin Darcy (2016)

Permanent URL: https://etd.library.emory.edu/concern/etds/5712m7288?locale=zh
Published

Abstract

Long-lasting protection is a hallmark of the adaptive immune response, and long- lived plasma cells have the capacity to produce neutralizing antibodies for as long as a lifetime. These antigen-specific, long-lived IgG plasma cells develop following exposure to antigen, along with T cell help. This T cell interaction leads to the formation of germinal centers, where activated B cells undergo class- switching and affinity maturation to generate high-affinity, long-lived IgG plasma cells and memory B cells.

Here we describe an alternative pathway of plasma cell development that can occur in the absence of germinal centers, in which plasma cells are not class- switched but are somatically mutated. These activation induced cytidine deaminase-induced (AID) mutations are less frequent than in IgG plasma cells, and surprisingly they are observed within the antibody framework rather than within the antigen-binding regions (CDRs). The resulting IgM plasma cells are likely of mixed affinity, compared to the clonally selected, high-affinity IgG plasma cells.

The long-lived IgM plasma cells originate from the B1 compartment, and are distinct from natural IgM cells. Unlike long-lived IgG plasma cells, which are resident in the bone marrow, IgM plasma cells persist within the red pulp of the spleen. They develop early in the immune response - prior to germinal center formation and the development of long-lived IgG plasma cells. Further, IgM plasma cells alone are sufficient to protect against viral challenge, even in the absence of IgG and memory B and T cells. Finally, we discuss the evolution and functionality of this long-lived IgM pathway, and the potential significance of these IgM plasma cells to rational vaccine design.

Table of Contents

Abstract Acknowledgements Chapter 1: Introduction....................................................................... 1 The B cell repertoire................................................................... 1

B cell activation and differentiation............................................ 3

Figure 1: Model of B cell differentiation........................................ 4

Figure 2: High frequency of mutations in CDRs following antigen-selection 10

B cell trafficking and survival.................................................. 10

B1 B cells................................................................................ 14

The evolution of humoral immunity......................................... 17

B cells in clinical disease............................................................ 18

The importance of antibody response in vaccine design................ 22

Summary............................................................................... 23

Literature Cited...................................................................... 24

Chapter 2: Long-lived, antigen-induced IgM plasma cells demonstrate somatic mutations and contribute to long-term protection....................................................................................................... 36

Figure 1: Expanded populations of IgM plasma cells persist in the spleen in response to diverse immunogens and pathogens.............................................................................................. 65

Figure 2: Antigen-specific, long-lived IgM plasma cells persist post-adoptive transfer and preferentially localize in the spleen, IgG plasma cells localize in the bone marrow................... 67

Figure 3: IgM plasma cells show evidence of somatic hypermutation, even when germinal centers are ablated 69

Figure 4: IgM heavy chain mutations are predominantly transitions and found in AID hotspot motifs, are AID-induced and AID-dependent........................................................................ 71

Figure 5: IgM heavy chain mutations are not enriched in CDR regions, unlike IgG, and show no evidence of antigen-selection................................................................................. 73

Figure 6: Germinal center independent IgM plasma cells are capable of neutralizing influenza virus in vitro and protecting the animal against infection in vivo........................................... 74

Figure 7: IgM plasma cells are capable of protecting the animal against infection in vivo in the absence of IgG plasma cells, memory B cells, and T cell help................................................. 76

Supplementary Table 1: Total heavy chain sequences with >90% homology to IgHV186.2 78

Supplementary Figure 1: Antigen-specific IgM and IgG titers persist, post-adoptive transfer of plasma cells into recipient Rag-/- mice............................................................................. 79

Supplementary Figure 2: Long-lived IgM, but not IgG, plasma cells are generated when germinal center formation is blocked by Cobra Venom Factor (CVF) treatment....................... 80

Supplementary Figure 3: Treatment with anti CD4 and CD8 antibodies leads to efficient depletion of CD4 and CD8 T cell.............................................................................................. 81

Literature Cited...................................................................... 82

Chapter 3: B1b B cells give rise to long-lived IgM plasma cells early in immune response 86

Figure 1: Long-lived IgM plasma cells require early T cell help but not germinal center formation, arise early in immune response............................................................................... 104

Figure 2: Plasma cells localize to the red pulp of the spleen, and only bind NP22CGG in immunized mice 105

Figure 3: Differential expression of chemokine and survival receptors on the surface of IgG and IgM long-lived plasma cells............................................................................................ 107

Figure 4: Figure 4: B1b, not B2, cells give rise to long-lived IgM plasma cells, even in the absence of germinal centers 109

Figure 5: Long-lived IgM arises early in immune response.......... 111

Supplementary Figure 1: B1b B cells proliferate only modestly in response to stimulation when compared to B2 cells 112

Literature Cited ..................................................................... 113

Chapter 4: Discussion...................................................................... 116

A new model of plasma cell development................................. 116

Figure 1: Model of B1-derived and B2-derived plasma cell differentiation pathways 119

The role of long-lived IgM plasma cells..................................... 120

Potential for clinical applications............................................ 126

Future directions of this study................................................ 129

Literature Cited 131

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