Item Details

title

REGULATION OF B CELL RESPONSES TO T-INDEPENDENT TYPE TWO ANTIGENS

author

Spurrier, Meghan

abstract

Polysaccharide (PS) antigens (Ags) are of high clinical relevance as many pathogens (including bacteria, fungi, parasites, and viruses) express polysaccharides on their surface. These antigens often behave as T-independent type 2 (TI-2) Ags which can elicit B cell responses in the absence of cognate MHC class II T cell help. Several vaccines targeting these types of polysaccharide antigens are currently available, including the Streptococcus pneumoniae vaccine, Pneumovax23. Despite the use of PS-based vaccines for more than 4 decades, there is still considerable gaps in our understanding of how B cell responses occur and are regulated during a TI-2 response. In order to improve current vaccines, we need to identify the regulatory pathways that influence TI-2 B cell regulation. My research has focused on factors regulating TI-2 antigen specific B cell activation, memory cell generation, and antibody production. In this study, we identified that PD-1 expression on B cells and PDL1 expression on non-Ag B cells limits TI-2 antigen-specific memory B cell generation. During secondary antigen encounter memory B cells expressing PD-1 and PDL2, as well as non-Ag specific non B cells expressing PDL1 and PDL2 limited the activation of memory B cells thus leading to reduced antibody secreting cell (ASC) generation and antibody (Ab) production. Thus, we identified a novel role for the PD1-PDL pathway in regulating primary and secondary B cell responses to TI-2 antigens. We also identified the requirement for B-cell intrinsic IFNAR expression in generating optimal TI-2 B cell responses. IFNAR-/- mice exhibit suboptimal antibody responses to Pneumovax23, as well as the synthetic haptenated polysaccharide TNP-Ficoll. Despite the positive effects of type one interferon (IFN-1) on B cells during the initial response to TI-2 antigens, we found that IFN-1 induced during a virus infection caused a loss in TI-2 antigen-specific IgG and IgG+ ASC in the spleen. This loss was associated with increases in apoptotic IgG+ plasmablasts. We also identified that generation of a newly-formed splenic plasmablast population leads to the loss in pre-existing TI-2 antigen-specific IgG suggesting that competition for space in the spleen likely contributes to the loss in IgG. In summary, our work demonstrates PD1-PDL regulation and IFNAR signaling represents two pathways that strongly influence TI-2 B cell responses. Our findings serve to advance the understanding of the regulation of these responses, especially in regards to the generation and maintenance of memory and antibody secreting B cells.

subject

B cell

IFNAR

Influenza

PD1

Streptococcus pneumoniae

TI-2 antigen

contributor

Haas, Karen M (committee chair)

Alexander-Miller, Martha (committee member)

Grayson, Jason (committee member)

Lyles, Douglas (committee member)

Ornelles, David (committee member)

date

2022-01-15T09:35:23Z (accessioned)

2022 (issued)

degree

Microbiology & Immunology (discipline)

embargo

2027-01-14 (terms)

2027-01-14 (liftdate)

identifier

http://hdl.handle.net/10339/99377 (uri)

language

en (iso)

publisher

Wake Forest University

type

Dissertation