Plasma cells: You are what you eat

Abstract

Plasma cells are terminally differentiated B lymphocytes that constitutively secrete antibodies. These antibodies can provide protection against pathogens, and their quantity and quality are the best clinical correlates of vaccine efficacy. As such, plasma cell lifespan is the primary determinant of the duration of humoral immunity. Yet dysregulation of plasma cell function can cause autoimmunity or multiple myeloma. The longevity of plasma cells is primarily dictated by nutrient uptake and non-transcriptionally regulated metabolic pathways. We have previously shown a positive effect of glucose uptake and catabolism on plasma cell longevity and function. In this review, we discuss these findings with an emphasis on nutrient uptake and its effects on respiratory capacity, lifespan, endoplasmic reticulum stress, and antibody secretion in plasma cells. We further discuss how some of these pathways may be dysregulated in multiple myeloma, potentially providing new therapeutic targets. Finally, we speculate on the connection between plasma cell intrinsic metabolism and systemic changes in nutrient availability and metabolic diseases.

Keywords: glucose; glutamine; metabolism; multiple myeloma; plasma cell.

Figure 1:. Mouse plasma cell subsets and markers.

BM: bone marrow. +/− indicates that a fraction of the cells are positive for the marker.

Figure 2:. Metabolic cues direct plasma cell longevity and function.

Schematic representation of the metabolic differences between short- and long-lived plasma cells (SLPCs and LLPCs). (A) Despite exhibiting similar transcriptomes, LLPCs take up higher levels of glucose and glutamine than do SLPCs under homeostatic conditions. Nutrients can also be provided through autophagy, which is also higher in LLPCs. These nutrients collectively are catabolized and directed to mitochondria for ATP generation, or used in synthesis and glycosylation of antibodies. ER stress is equivalent between plasma cell subsets, but SLPCs degrade antibody molecules more than LLPCs. As a result, LLPCs secrete more antibody molecules than SLPCs, despite equivalent rates of protein and antibody synthesis. (B) Under limiting nutrient availability and low ATP generation, LLPCs can expand their basal respiratory capacity to compensate. SLPCs are unable to perform this function and as a result, initiate pathways of programmed cell death.