In vitro identification of human pro-B cells that give rise to macrophages, natural killer cells, and T cells

Abstract

IntroductionEarly stages of human B-cell development can be identified by the expression of cytoplasmic and cell-surface markers and the ordered rearrangements of the V, D, and J gene segments that encode the variable domain of the immunoglobulin heavy-chain (IgH) locus. 1 Thus, D3J H rearrangements in pro-B cells precede the V3DJ H rearrangement in pre-B cells. The earliest B-cell precursors that carry a complete VDJ H rearrangement have been identified by their intracellular expression of a chain without light (L) chain. These pre-B cells express the CD10 and CD19 antigens and the chain associated with a surrogate light chain coded by the 5/14.1 and VpreB genes. 2 More primitive pro-B cells recognized by their expression of CD34, CD19, and CD10 antigens carry a DJ H rearrangement, which can be transcribed. More recently, CD19 Ϫ cells have been isolated from fresh bone marrow, which expresses the B-cell receptor (BCR)-associated molecule CD79a or Vpre-B proteins and a DJ H rearrangement. [3][4][5][6] This suggests that the B-cell program can be activated prior to the expression of the CD19 antigen and VDJ H rearrangement. How multipotent stem cells progressively restrict their potential to a B-cell fate has been best studied in mice deleted of key control genes, such as E2A, EBF, Absence of the first 2 arrest B-cell differentiation prior to the DJ H rearrangement, whereas typical B220 ϩ c-Kit ϩ pro-B cells, which have initiated DJ H rearrangement and express Rag-1, Rag-2, TdT, 5, VpreB, E2A, and EBF, can be isolated from the bone marrow of Pax-5 Ϫ/Ϫ mice. Despite their pro-B phenotype, these cells can differentiate into macrophages, osteoclasts, dendritic cells, natural killer (NK) cells, T cells, granulocytic cells and erythroid cells in vitro and in vivo, when exposed to the appropriate conditions. 10,11 On the basis of these observations, it has been proposed that the B-cell program is first activated in a "multipotent" cell and that the function of Pax-5 is to repress the myeloid and T-cell genes and restrict cells to a B-cell fate. 12,13 Even though this 2-step pattern has not been demonstrated using primary cells or wild-type mice, a close proximity exists between B-lymphoid, macrophages, and osteoclast lineages in healthy mice, [14][15][16] perhaps controlled by the relative levels of Pu.1 and Pax-5. 17,18 Investigating human B-cell differentiation is hampered both by the low proliferation rate of human pro-B cells 8,19 and the small number of markers recognizing early-B cells, as opposed to those available in mice (B220, CD43, CD24, c-Kit, AA4.1). [20][21][22] Furthermore, reproducible conditions to grow human B-cell progenitors in vitro have been described only recently. High numbers of CD34 Ϫ CD19 ϩ CD10 ϩ sIgM Ϫ pre-B cells that express Pax-5, -like, and transcripts are obtained 23 in cocultures of cord bloodderived CD34 ϩ cells on murine feeders. [23][24][25][26][27][28] Human B-cell differentiation can also be obtained in vivo in NOD-SCID (nonobese diabetic severe combined immunodeficient) mice inj...

IgH DJ rearrangements within T-ALL correlate with cCD79a expression, an immature/TCRγδ phenotype and absence of IL7Rα/CD127 expression

“…Strikingly, IgH rearrangements and CD127 expression were mutually exclusive, particularly within the gd/IM lineage, when Ig rearrangements were seen in 11/17 (65%) CD127 negative compared to only 2/15 (13%) CD127 positive cases; P ¼ 0.003. This is in keeping with IL7-mediated orientation towards a T/NK/dendritic-macrophage precursor, as recently described, 15 rather than towards the B-cell lineage. Among gd/IM T-ALLs, only 2/14 cCD79a þ /IgH D-J þ cases were CD127 þ compared to seven of the 11 cCD79aÀ/IgH D-J-cases (P ¼ 0.02).…”

“…1,14 An early CD34 þ , CD19À, CD10À, cCD79a þ , CD127 þ cord blood B progenitor has recently been shown to demonstrate IgH DJ rearrangement and macrophage, natural killer (NK), B and T lymphoid potential. 15 IgH DJ rearrangements have also been reported in normal immature murine, 16 but not human, 12 thymocytes and in 22% of pediatric T-ALLs, particularly in TCRgd þ cases. 17 We have recently described a TCR-based classification which allows separation of T-ALLs into ab-lineage (TCRab/cTCRb expressing and/or TCRb VDJ rearranged T-ALLs) and gd lineage/immature (gd/IM) leukemias (TCRgd expressing or absence of complete TCRb rearrangement).…”

Reprogramming of human postmitotic neutrophils into macrophages by growth factors

“…A recent report stated that human B-cell progenitors obtained from cultures of cord blood CD34 ϩ CD10 Ϫ CD19 Ϫ cells gave rise to macrophages, NK cells, and T cells when exposed to the appropriate culture conditions. 23 Our study shows the lineage switch of human primary postnatal cells and further extends the existence of lineage switch to postmitotic cells. This notion is also supported by our observations in the microarray analysis that gene expression profiles of the resultant cells differed from those of the starting CD15 ϩ CD14 Ϫ neutrophils and were similar to those of CD14 ϩ cell-derived macrophages.…”

“…22 Thus, normal murine lymphoid progenitors may retain the potential to differentiate into macrophages. Reynaud et al 23 reported that human cord blood-derived pro-B cells with DJ H rearrangements of the immunoglobulin (Ig) locus generate macrophages, NK cells, and T cells. However, it is unknown whether the lineage switch occurs in normal human mature hematopoietic cells.…”

Clonally related follicular lymphomas and histiocytic/dendritic cell sarcomas: evidence for transdifferentiation of the follicular lymphoma clone

“…For example, it has been shown that human pro-B cells can give rise to macrophages in vitro. 6 Rare cases of H/DC neoplasms have been reported in patients with mature B-cell neoplasms. Vasef et al reported 3 patients with dendritic cell tumors associated with low-grade B-cell malignancies, 7 including a 59-year-old woman who developed a dendritic cell sarcoma 9 years following a diagnosis of follicular lymphoma (FL), grade 1.…”