Lineage infidelity in myeloid cells with TCR gene rearrangement: A latent developmental potential of proT cells revealed by ectopic cytokine receptor signaling

The most immature lymphoid-committed progenitors in both the bone marrow (common lymphoid progenitor) and thymus (proT1) maintain a latent granulocyte/macrophage (G/M) differentiation potential that can be initiated by signals emanating from exogenously expressed IL-2 receptors. In this study, we investigate at which developmental stage thymocytes lose this G/M differentiation potential. We demonstrate that the next maturational stage after proT1 cells (proT2), but not preT (TN3) cells, can convert cell fate from lymphoid to myeloid in response to ectopic IL-2 receptor signaling in human IL-2Rβ transgenic mice. It is significant that approximately 10% of clonogenic G/M colonies derived from proT cells of IL-2Rβ transgenic mice have DJ rearrangement specifically at the Dβ1 but not Dβ2 segment in the TCRβ locus. No TCR gene rearrangement is observed in G/M cells from nontransgenic mice, suggesting that the G/M cells we observe in this system were truly lymphoid-committed before stimulation with IL-2. In addition, Dβ1 and Dβ2 DJ rearrangement of the TCRβ gene may be differentially regulated and thus serve as markers for distinct proT cell maturational stages.

[1]  Stuart H. Orkin,et al.  Diversification of haematopoietic stem cells to specific lineages , 2000, Nature Reviews Genetics.

[2]  I. Weissman,et al.  Cell-fate conversion of lymphoid-committed progenitors by instructive actions of cytokines , 2000, Nature.

[3]  I. Weissman,et al.  A clonogenic common myeloid progenitor that gives rise to all myeloid lineages , 2000, Nature.

[4]  I. Weissman,et al.  Translating stem and progenitor cell biology to the clinic: barriers and opportunities. , 2000, Science.

[5]  Stephen L. Nutt,et al.  Commitment to the B-lymphoid lineage depends on the transcription factor Pax5 , 1999, Nature.

[6]  E. Oltz,et al.  An inducible cell model for studies of V(D)J recombinational control. , 1999, Journal of immunological methods.

[7]  D. Metcalf.  Stem Cells, Pre‐Progenitor Cells and Lineage‐Committed Cells: Are Our Dogmas Correct? , 1999, Annals of the New York Academy of Sciences.

[8]  Jianzhu Chen,et al.  Control of V(D)J Recombinational Accessibility of the Dβ1 Gene Segment at the TCRβ Locus by a Germline Promoter , 1999 .

[9]  D. Schatz,et al.  Characterization of TCR gene rearrangements during adult murine T cell development. , 1999, Journal of immunology.

[10]  R. Hardy,et al.  Commitment to the B Lymphoid Lineage Occurs before DH-JH Recombination , 1999, The Journal of experimental medicine.

[11]  L. Glimcher,et al.  Transcription Factors in Lymphocyte Development— T and B Cells Get Together , 1999, Cell.

[12]  R. Hockett,et al.  Kinetics of T cell receptor β, γ, and δ rearrangements during adult thymic development: T cell receptor rearrangements are present in CD44+CD25+ Pro-T thymocytes , 1998 .

[13]  A. Michie,et al.  Early intrathymic precursor cells acquire a CD4(low) phenotype. , 1998, Journal of immunology.

[14]  I. Weissman,et al.  Identification of Clonogenic Common Lymphoid Progenitors in Mouse Bone Marrow , 1997, Cell.

[15]  M. Schlissel,et al.  Accessibility and the developmental regulation of V(D)J recombination. , 1997, Seminars in immunology.

[16]  K. Shortman,et al.  Thymic dendritic cell precursors: relationship to the T lymphocyte lineage and phenotype of the dendritic cell progeny , 1996, The Journal of experimental medicine.

[17]  A. Shaffer,et al.  Cell Type–Specific Chromatin Structure Determines the Targeting of V(D)J Recombinase Activity In Vitro , 1996, Cell.

[18]  K. Sugamura,et al.  Differences in the interleukin‐2 (IL‐2) receptor system in human and mouse: α chain is required for formation of the functional mouse IL‐2 receptor , 1995, European journal of immunology.

[19]  T. Moore,et al.  T-cell lineage commitment and cytokine responses of thymic progenitors. , 1995, Blood.

[20]  H. Fehling,et al.  Crucial role of the pre-T-cell receptor α gene in development of ap but not γδ T cells , 1995, Nature.

[21]  T. Honjo,et al.  IL-2 can support growth of CD8+ T cells but not CD4+ T cells of human IL-2 receptor beta-chain transgenic mice. , 1994, Journal of immunology.

[22]  K. Sugamura,et al.  Expression of the mouse interleukin‐2 receptor γ chain in various cell populations of the thymus and spleen , 1994, European journal of immunology.

[23]  S. Tonegawa,et al.  Onset of TCR-beta gene rearrangement and role of TCR-beta expression during CD3-CD4-CD8- thymocyte differentiation. , 1994, Journal of immunology.

[24]  K. Arai,et al.  Sharing of the interleukin-2 (IL-2) receptor gamma chain between receptors for IL-2 and IL-4. , 1993, Science.

[25]  S. Nishikawa,et al.  Characterization of c-kit positive intrathymic stem cells that are restricted to lymphoid differentiation , 1993, The Journal of experimental medicine.

[26]  A. Zlotnik,et al.  A developmental pathway involving four phenotypically and functionally distinct subsets of CD3-CD4-CD8- triple-negative adult mouse thymocytes defined by CD44 and CD25 expression. , 1993, Journal of immunology.

[27]  Li Wu,et al.  Thymic dendritic cells and T cells develop simultaneously in the thymus from a common precursor population , 1993, Nature.

[28]  S. Tonegawa,et al.  Mutations in T-cell antigen receptor genes α and β block thymocyte development at different stages , 1992, Nature.

[29]  N. Tanaka,et al.  Cloning of the gamma chain of the human IL-2 receptor. , 1992, Science.

[30]  V. Stewart,et al.  RAG-2-deficient mice lack mature lymphocytes owing to inability to initiate V(D)J rearrangement , 1992, Cell.

[31]  Susumu Tonegawa,et al.  RAG-1-deficient mice have no mature B and T lymphocytes , 1992, Cell.

[32]  M. Antica,et al.  Developmental potential of the earliest precursor cells from the adult mouse thymus , 1991, The Journal of experimental medicine.

[33]  C. Sherr,et al.  Macrophage lineage switching of murine early pre-B lymphoid cells expressing transduced fms genes , 1990, Molecular and cellular biology.

[34]  W. Alexander,et al.  Hemopoietic lineage switch: v-raf oncogene converts Eμmyc transgenic B cells into macrophages , 1988, Cell.

[35]  M. Minden,et al.  T cell receptor and immunoglobulin gene rearrangements in acute myeloblastic leukemia , 1986, The Journal of experimental medicine.

[36]  A. Palumbo,et al.  Lineage infidelity of a human myelogenous leukemia cell line. , 1984, Blood.

[37]  M. Minden,et al.  Immunoglobulin gene rearrangement in acute myelogenous leukemia. , 1984, Cancer research.

[38]  D. Schatz,et al.  Factors and forces controlling V(D)J recombination. , 2001, Advances in immunology.

[39]  Li Wu,et al.  Early T lymphocyte progenitors. , 1996, Annual review of immunology.

[40]  F. Alt,et al.  Accessibility control of antigen-receptor variable-region gene assembly: role of cis-acting elements. , 1996, Annual review of immunology.

[41]  I. Weissman,et al.  The biology of hematopoietic stem cells. , 1995, Annual review of cell and developmental biology.

[42]  I. Weissman,et al.  Early events in T-cell maturation. , 1987, Annual review of immunology.