c-Myc downregulation is usually a crucial event leading to the expression of Glycogen synthase kinase 3 (GSK-3), which in turn promotes glycolysis, mitochondrial biogenesis, and ROS formation in proliferating B cells 80

c-Myc downregulation is usually a crucial event leading to the expression of Glycogen synthase kinase 3 (GSK-3), which in turn promotes glycolysis, mitochondrial biogenesis, and ROS formation in proliferating B cells 80. The rapid proliferation and nutrient consumption within GC B cells potentially render them susceptible to starvation-induced cell death. 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. expression, a common subunit of multiple amino acid transporters 54, 55. In addition to glutamine, this transporter is crucial for the uptake of multiple large neutral amino acids, which are substrates for protein synthesis and feed into other metabolic pathways 56. While SLC3A2 pairs with SLC7A5 to form CD98, it can also pair with SLC1A5 to make up the ASCT2 transporter, both of which facilitate the uptake of large neutral amino acids by B cells 57. Sstr1 Glutamine can feed into the TCA cycle as -ketoglutarate, thereby acting as an anaplerotic substrate to replenish TCA cycle intermediates 53. Through the TCA cycle, glutamine MC-GGFG-DX8951 can be used to generate other amino acids such as glutamate and aspartate, citrate for use in lipogenic pathways, and succinate which is usually oxidized to provide electrons for respiration and ATP generation 23. The uptake of both glucose and glutamine are tightly regulated processes and are controlled by expression of the microRNA let-7, which suppresses expression of Hexokinase-2 and c-Myc 58. In addition to these nutrients, leucine uptake promotes mTORC1 activation in B cells 59. Thus, activation signals promote nutrient uptake to allow B cells to expand and divide. After exposure to the antigen and initiating activation programs, B cells migrate towards interface between the T and B cell zones in the secondary lymphoid organ to recruit help from T cells 60. T cells in turn, through recognition of the peptide-MHC-II complex on the surface of B cells, provide help to B cells in the form of costimulatory interactions involving CD154-CD40, ICOS-ICOSL, OX40-OX40L, LFA-2-ICAM-1 as well as through secretion of cytokines and growth factors 61. These initial interactions enable B cells to subsequently undergo proliferate and form foci at the outer edges of the B cell follicles MC-GGFG-DX8951 62. Some of these cells may undergo isotype switching and differentiate into short-lived plasma cells and contribute to the early humoral response while others can form memory B cells 63, 64. Alternatively, some B cells migrate to the centers of B cell follicles and establish germinal centers (GCs) 65. 2.3. Germinal centers Depending on the contamination or immunization, GCs can be detected as early as 3 days post-immunization and can persist for many weeks 66C69. The GC is usually organized into a dark zone, consisting of highly proliferative B cells, and a light zone MC-GGFG-DX8951 comprised of non-dividing B cells 70. Within the germinal centers, B cells express activation-induced cytidine deaminase (AID), which is responsible for both somatic hypermutation and immunoglobulin isotype-switching 71. Dark-zone GC B cells proliferate rapidly while accumulating somatic mutations in antibody receptor-encoding genes 72, 73. These cells then migrate to the light zone where they compete among themselves for antigen, which is usually endocytosed and subsequently offered through MHCII to T cells in an attempt to procure survival signals 73. Only a small fraction of these cells are selected in the light zone and subsequently return to the dark zone undergo more rounds of proliferation, class switching, and affinity maturation. Much of the proliferative burst in the dark zone has been shown to rely on c-Myc, as its ablation prospects to total abrogation of GCs 74, 75. c-Myc is usually induced in GC B cells by the action of BCR and CD40 signals 76. Signals through the B cell receptor and CD40 MC-GGFG-DX8951 also induce mTOR activation, thereby permitting B.