Regulation of B-lineage specification by the IL-7/JAK3/STAT5 pathway (83.6)

Abstract

Abstract The cytokine IL-7 is essential for early B cell development in adult bone marrow. We previously showed that B cell genesis arrests at the common lymphoid progenitor (CLP) stage in mice lacking the common gamma chain or the alpha-chain of the IL-7 receptor (IL-7R). Other studies suggest that CLPs are enriched for B-lineage specified (but uncommitted) precursors, as CLPs are not requisite for T cell development, and V(D)J recombinase activity in CLPs requires a B-specific enhancer element in the RAG locus. Here we probe events downstream of the IL-7R that promote B-lineage specification. We find that JAK3, the principal kinase downstream of the IL-7R, is essential for B cell development beyond the CLP stage. We further demonstrate that JAK3-deficient CLPs exhibit a dramatic loss in RAG1/2 expression and V(D)J recombinase activity. JAK3-null CLPs also lacked transcripts for EBF1, a B-lineage restricted transcription factor previously suggested to promote RAG expression. We also find that conditional inactivation of STAT5, the key transcription factor activated by JAK3, results in loss of B-lineage precursors beyond the CLP and diminished V(D)J recombinase activity. Together these data suggest that IL-7R activation of the JAK3/STAT5 pathway plays a key role in initiating several molecular events required for early B cell development in CLPs.