Long-term in vivo reconstitution of T-cell development by Pax5-deficient B-cell progenitors

The mechanisms controlling the commitment of haematopoietic progenitors to the B-lymphoid lineage are poorly understood. The observations that mice deficient in E2A(1,2) and EBF3 lack B-lineage cells have implicated these two transcription factors in the commitment process. Moreover, the expression of genes encoding components of the rearrangement machinery (RAG1, RAG2, TdT) or pre-B-cell receptor (lambda 5, VpreB, Ig alpha, Ig beta) has been considered to indicate B-lineage commitment(4). All these genes including E2A and EBF are expressed in pro-B cells lacking the transcription factor Pax5 (refs 5-7). Here we show that cloned Pax5-deficient pro-B cells transferred into RAG2-deficient mice provide longterm reconstitution of the thymus and give rise to mature T cells expressing alpha/beta-T-cell receptors. The bone marrow of these mice contains a population of cells of Pax5(-/-) origin with the same phenotype as the donor pro-B cells. When transferred into secondary recipients, these pro-B cells again home to the bone marrow and reconstitute the thymus. Hence, B-Lineage commitment is determined neither by immunoglobulin DJ rearrangement nor by the expression of E2A, EBF, lambda 5, VpreB, Ig alpha and Ig beta. Instead, our data implicate Pax5 in the control of B-lineage commitment.