Research ArticleHUMORAL IMMUNITY

R-Ras2 is required for germinal center formation to aid B cells during energetically demanding processes

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Sci. Signal.  29 May 2018:
Vol. 11, Issue 532, eaal1506
DOI: 10.1126/scisignal.aal1506

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R-Ras2 revs replication

Germinal centers are specialized lymphoid structures that facilitate the development of high-affinity antibody responses by B cells, a process that requires the guanosine triphosphate hydrolase activity of Ras family members. Mendoza et al. characterized germinal center formation in mice lacking R-Ras2 or other related family members and found that Ras proteins are functionally specialized. Only B cell–intrinsic R-Ras2 activity was necessary for cellular proliferation and germinal center development. R-Ras2 deficiency specifically reduced the expression of mitochondrial tRNAs necessary for mitochondrial replication and glucose metabolism in B cells. These data suggest that R-Ras2 signaling is essential for the metabolic reprograming of germinal center B cells to supply the energy required to generate effective antibody responses.

Abstract

Upon antigen recognition within peripheral lymphoid organs, B cells interact with T cells and other immune cells to transiently form morphological structures called germinal centers (GCs), which are required for B cell clonal expansion, immunoglobulin class switching, and affinity maturation. This process, known as the GC response, is an energetically demanding process that requires the metabolic reprogramming of B cells. We showed that the Ras-related guanosine triphosphate hydrolase (GTPase) R-Ras2 (also known as TC21) plays an essential, nonredundant, and B cell–intrinsic role in the GC response. Both the conversion of B cells into GC B cells and their expansion were impaired in mice lacking R-Ras2, but not in those lacking a highly related R-Ras subfamily member or both the classic H-Ras and N-Ras GTPases. In the absence of R-Ras2, activated B cells did not exhibit increased oxidative phosphorylation or aerobic glycolysis. We showed that R-Ras2 was an effector of both the B cell receptor (BCR) and CD40 and that, in its absence, B cells exhibited impaired activation of the PI3K-Akt-mTORC1 pathway, reduced mitochondrial DNA replication, and decreased expression of genes involved in glucose metabolism. Because most human B cell lymphomas originate from GC B cells or B cells that have undergone the GC response, our data suggest that R-Ras2 may also regulate metabolism in B cell malignancies.

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