A self-reinforcing regulatory network triggered by limiting IL-7 activates pre-BCR signaling and differentiation

K Ochiai, M Maienschein-Cline, M Mandal… - Nature …, 2012 - nature.com
K Ochiai, M Maienschein-Cline, M Mandal, JR Triggs, E Bertolino, R Sciammas, AR Dinner
Nature immunology, 2012nature.com
The molecular crosstalk between the interleukin 7 receptor (IL-7R) and the precursor to the
B cell antigen receptor (pre-BCR) in B lymphopoiesis has not been elucidated. Here we
demonstrate that in pre-B cells, the IL-7R but not the pre-BCR was coupled to
phosphatidylinositol-3-OH kinase (PI (3) K) and the kinase Akt; signaling by this pathway
inhibited expression of recombination-activating gene 1 (Rag1) and Rag2. Attenuation of IL-
7 signaling resulted in upregulation of the transcription factors Foxo1 and Pax5, which …
Abstract
The molecular crosstalk between the interleukin 7 receptor (IL-7R) and the precursor to the B cell antigen receptor (pre-BCR) in B lymphopoiesis has not been elucidated. Here we demonstrate that in pre-B cells, the IL-7R but not the pre-BCR was coupled to phosphatidylinositol-3-OH kinase (PI(3)K) and the kinase Akt; signaling by this pathway inhibited expression of recombination-activating gene 1 (Rag1) and Rag2. Attenuation of IL-7 signaling resulted in upregulation of the transcription factors Foxo1 and Pax5, which coactivated many pre-B cell genes, including Rag1, Rag2 and Blnk. Induction of Blnk (which encodes the signaling adaptor BLNK) enabled pre-BCR signaling via the signaling molecule Syk and promoted immunoglobulin light-chain rearrangement. BLNK expression also antagonized Akt activation, thereby augmenting the accumulation of Foxo1 and Pax5. This self-reinforcing molecular circuit seemed to sense limiting concentrations of IL-7 and functioned to constrain the proliferation of pre-B cells and trigger their differentiation.
nature.com