Entry into the Thymic Microenvironment Triggers Notch Activation in the Earliest Migrant T Cell Progenitors 1

Interactions between T cell precursors and thymic stromal cells are essential during thymocyte development. However, the role of the thymus in initial commitment of lymphoid progenitors to the T lineage remains controversial, with data providing evidence for both extra- and intrathymic commitment mechanisms. In this context, it is clear that Notch1 is an important mediator during initiation of T cell development. Here we have analyzed the mechanisms regulating Notch activation in lymphoid precursors at extrathymic sites and in the thymus, including stages representing the first wave of embryonic thymus colonization on embryonic day 12 of gestation. We show that Notch activation in migrant lymphoid precursors requires entry into the thymic microenvironment where they are exposed to Notch ligands expressed by immature thymic epithelial cells. Moreover, continued Notch signaling in such precursors requires sustained interactions with Notch ligands. Collectively, these findings suggest a role for Notch in an intrathymic mechanism of T cell lineage commitment involving sustained interactions with Notch ligand bearing thymic epithelium.

[1]  H. Macdonald,et al.  Inactivation of Notch1 impairs VDJbeta rearrangement and allows pre-TCR-independent survival of early alpha beta Lineage Thymocytes. , 2002, Immunity.

[2]  M. Bevan,et al.  Correlating notch signaling with thymocyte maturation. , 1998, Immunity.

[3]  J. Aster,et al.  Notch1 expression in early lymphopoiesis influences B versus T lineage determination. , 1999, Immunity.

[4]  J. Zúñiga-Pflücker,et al.  Requirement for the Thymus in αβ T Lymphocyte Lineage Commitment , 1998 .

[5]  K. Ohmura,et al.  T cell progenitors emerge earlier than B cell progenitors in the murine fetal liver. , 2000, Immunity.

[6]  E. Jenkinson,et al.  Factors regulating stem cell recruitment to the fetal thymus. , 1999, Journal of immunology.

[7]  William J. Ray,et al.  A presenilin-1-dependent γ-secretase-like protease mediates release of Notch intracellular domain , 1999, Nature.

[8]  S. Egan,et al.  Subversion of the T/B lineage decision in the thymus by lunatic fringe-mediated inhibition of Notch-1. , 2001, Immunity.

[9]  E. Jenkinson,et al.  Studies on the phenotype of migrant thymic stem cells , 1999, European journal of immunology.

[10]  G. Anderson,et al.  Lymphostromal interactions in thymic development and function , 2001, Nature Reviews Immunology.

[11]  H. Macdonald,et al.  Notch 1–Deficient Common Lymphoid Precursors Adopt a B Cell Fate in the Thymus , 2001, The Journal of experimental medicine.

[12]  J. Aster,et al.  Deltex1 redirects lymphoid progenitors to the B cell lineage by antagonizing Notch1. , 2002, Immunity.

[13]  B. Osborne,et al.  Notch and the immune system. , 1999, Immunity.

[14]  H. Macdonald,et al.  Deficient T cell fate specification in mice with an induced inactivation of Notch1. , 1999, Immunity.

[15]  Boris Reizis,et al.  Direct induction of T lymphocyte-specific gene expression by the mammalian Notch signaling pathway. , 2002, Genes & development.

[16]  K. Tomita,et al.  The bHLH gene Hes1 is essential for expansion of early T cell precursors. , 1999, Genes & development.

[17]  S. Korsmeyer,et al.  bcl-2 inhibits multiple forms of apoptosis but not negative selection in thymocytes , 1991, Cell.

[18]  J. Pongrácz,et al.  Notch ligand‐bearing thymic epithelial cells initiate and sustain Notch signaling in thymocytes independently of T cell receptor signaling , 2001, European journal of immunology.

[19]  G. Anderson,et al.  Analysis of cytokine gene expression in subpopulations of freshly isolated thymocytes and thymic stromal cells using semiquantitative polymerase chain reaction , 1993, European journal of immunology.

[20]  E. Jenkinson,et al.  An Essential Role for Thymic Mesenchyme in Early T Cell Development , 2000, The Journal of experimental medicine.

[21]  T. Kurosaki,et al.  BLNK: connecting Syk and Btk to calcium signals. , 2000, Immunity.

[22]  M. Bevan,et al.  Notch1 signaling promotes the maturation of CD4 and CD8 SP thymocytes. , 2000, Immunity.

[23]  G. Anderson,et al.  Thymic epithelial cells provide unique signals for positive selection of CD4+CD8+ thymocytes in vitro , 1994, The Journal of experimental medicine.

[24]  K. Ohmura,et al.  Direct evidence for the commitment of hematopoietic stem cells to T, B and myeloid lineages in murine fetal liver. , 1997, International immunology.

[25]  M. Haury,et al.  Differential Effects of Notch Ligands Delta-1 and Jagged-1 in Human Lymphoid Differentiation , 2001, The Journal of experimental medicine.

[26]  Y. Katsura.  Redefinition of lymphoid progenitors , 2002, Nature Reviews Immunology.

[27]  K. Kretzschmar,et al.  Identification of pro‐thymocytes in murine fetal blood: T lineage commitment can precede thymus colonization. , 1994, The EMBO journal.

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

[29]  G. Anderson,et al.  Studies on T cell maturation on defined thymic stromal cell populations in vitro , 1992, The Journal of experimental medicine.