Date of Award

Summer 8-15-2017

Author's School

Graduate School of Arts and Sciences

Author's Department

Biology & Biomedical Sciences (Immunology)

Degree Name

Doctor of Philosophy (PhD)

Degree Type

Dissertation

Abstract

Antibodies are an integral aspect of the immune response by binding and neutralizing antigens, and triggering other arms of the immune system. These antibodies are produced at a prodigious rate by plasmablasts and plasma cells. Plasmablasts and short- lived plasma cells (SLPCs) are generated during the initial stages of T cell-dependent antibody responses in extrafollicular regions of spleens and lymph nodes, but these cells are only thought to live for a number of days. Other antigen activated B cells enter germinal center reactions and undergo affinity maturation before selection into either the memory B cell or long-lived plasma cell (LLPC) pool. LLPCs reportedly can live for decades and it is these cells that generate the high- affinity neutralizing antibodies that mediate long-term humoral immunity. Yet, the biology that maintains this longevity is not understood.

Here, we identify a role for glucose in maintaining longevity and antibody production in plasma cells. Through bioenergetic profiling, we demonstrate that LLPCs can robustly engage pyruvate-dependent respiration whereas their short-lived counterparts cannot. LLPCs import more glucose than do SLPCs in vivo, and this glucose is essential for the generation of pyruvate. Glucose is primarily used to glycosylate antibodies, but glycolysis can be promoted by stimuli such as low ATP levels and the resultant pyruvate used for respiration by LLPCs. Deletion of Mpc2, which encodes an essential component of the mitochondrial pyruvate carrier, leads to a progressive loss of LLPCs and vaccine-specific antibodies in vivo. Thus, glucose uptake and mitochondrial pyruvate import prevent bioenergetic crises and allow LLPCs to provide enduring antibody-mediated immunity.

Subsequently, we identify differential glucose import by plasma cell populations in the spleen. Using variable glucose import and B220 expression, we identified four populations of plasma cells. Cells that imported higher amounts of glucose secreted more antibodies, had longer lifespans, and expressed higher amounts of the amino acid transporter CD98. Surprisingly, however, transcriptional profiling of these cell types showed little changes between the population and analysis of ER stress genes also did not greatly differ.

Taken together, we propose that the basis of plasma cell heterogeneity is minimally dependent on transcriptional profiles, and is instead dictated primarily by changes in metabolic pathways. Further work needs to be done to identify signals that promote increased glucose import by populations of plasma cells as well as key transporters that mediate glucose up take.

Language

English (en)

Chair and Committee

Deepta Bhattacharya

Committee Members

Paul M. Allen, Gwendolyn J. Randolph, Eugene M. Oltz, Brian N. Finck,

Comments

Permanent URL: https://doi.org/10.7936/K7R49Q5S

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Available for download on Wednesday, December 15, 2117

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