-
Views
-
Cite
Cite
Sarah A Greaves, Chiara Babolin, Raul M Torres, Roberta Pelanda, Ras, Erk, and PI3K signaling pathways in the central selection of B cells, The Journal of Immunology, Volume 198, Issue Supplement_1, May 2017, Page 202.6, https://doi.org/10.4049/jimmunol.198.Supp.202.6
Close - Share Icon Share
Abstract
B cell selection mechanisms in the bone marrow control the nature of the primary B cell repertoire, generating diverse specificities while reducing autoreactivity. Our studies aim to characterize the mechanisms that drive the positive selection of immature B cells in the bone marrow. It has been shown that the B cell receptor (BCR) is able to signal in the absence of ligand (tonic signal) and this signal is required for B cell development. We hypothesize that alterations in tonic signaling could cause aberrant positive selection of autoreactive immature B cells. We have previously shown that low levels of active Ras, Erk, and Akt correlate with levels of BCR tonic signal and that constitutive activation of Ras allows for differentiation of autoreactive immature B cells in vitro. We are currently testing the individual contributions of the Erk and PI3K pathways in this selection process. By using retroviral transduction of primary bone marrow B cells in vitro, we show that Erk activation can overcome a lack of tonic signaling to induce differentiation of nonautoreactive or slightly autoreactive B cells. We have also found that the Dual Specificity Phosphatase 5 (DUSP5), a novel phosphatase, may play a role in Erk regulation and the selection of immature B cells. In order to study these pathways in vivo we generated mouse models in which constitutively active forms of MEK or PI3K are specifically expressed in autoreactive B cells to determine if activation of these molecules is sufficient to bypass central tolerance. Preliminary data suggests that in vivo activation of PI3K can drive development of autoreactive B cells and allow some escape to the periphery.
