The Regulation and Role of L‐Glutamine in B‐cell Activation

Abstract

B cell activation is a highly energetic event that induces cell growth, rapid proliferation, and antibody production. Aberrant activation or expansion of these cells can lead to disease states such as lymphomas or autoimmune diseases. To meet the metabolic demands of this process, the cell induces rapid uptake of nutrients that can be utilized in cellular processes and macromolecule synthesis. We have investigated the role of the amino acid glutamine, which is emerging as a critical immunomodulatory nutrient, but the role of which in the B cell responses is poorly understood. Our data show that B cells are unable to increase cell size, increase total cellular protein levels, or engage in DNA synthesis in the absence of glutamine, however, very early activation events are unaffected by glutamine availability. The high affinity glutamine transporter protein, ASCT2, is rapidly upregulated at both the mRNA and protein level following B cell stimulation, indicating this transporter's involvement in the glutamine uptake process. Further, specific inhibition of ASCT2 by the small molecule GPNA induced defects in activation response similar to those induced by a lack of extracellular glutamine. Supplementation with high levels of extracellular leucine was shown to abate some of the defects associated with GPNA treatment, indicating the possibility of mTORC involvement as previously observed in T cells. Overall these data shed light on the glutamine requirement of B cells during the activation response, and indicate a possible underlying mechanism of growth regulation by mTORC.