1. Development of T Lymphocytes. Despite abundant information about maturational events amongst thymocytes, substantial controversy remains about the origins, functions, identities, and fate of recent thymic emigrants (RTE's) on the one hand and thymocyte progenitors (prothymocytes) on the other. To address these questions, we have described markers that uniquely define RTE's and permit their isolation in high degrees of purity. In addition, we have developed intravenous and intrathymic adoptive transfer assays and parabiotic animal models in which to demonstrate the existence of intrathymic microvascular gates and intrathymic microenvironmental niches (IMN) for prothymocytes in adult mice. Our recent work has led us to postulate the existence of a thymus-bone marrow feedback loop that regulates the generation and mobilization of thymocyte progenitors in/from the bone marrow in coordination with their periodic importation by the thymus.

2. Development of B Lymphocytes. We have devised a long-term lymphoid culture system that selectively supports the generation of B-lineage precursor cells from rat, mouse, and human bone marrow. We are using this culture system to identify stage-specific growth factors (cytokines) responsible for the growth and differentiation of these cells. Our results have implicated a unique hybrid cytokine comprised of Interleukin (IL)-7 and the b-chain of hepatocyte growth factor (HGFb) in selectively regulating the growth and differentiation of common lyphoid progenitors and pre-pro-B cells. Studies are in progress using IL-7 gene-deleted mice, to determine the mechanism of action of this novel growth factor. Our recent results indicate that the IL-7/HGFb hybrid cytokine acts by inducing juxtacrine interactions and signaling through the IL-7 and HGF receptors.

3. The Role of the Thymus in Dominant (Active) Tolerance. Although the generation of immunoregulatory thymocytes (THYreg) was first observed more than three decades ago, only indirect evidence had been provided for their export to the peripheral lymphoid tissues. We have observed several instances in which RTEs induce systemic tolerance to autoimmune and autologous graft-versus-host disease and suppress ongoing immune responses to non-self antigens. Some of these regulatory RTE have a CD4+ CD25+ phenotype and others a CD4+ CD8- NK1.1+ phenotype. Our results have demonstrated that the export of RTEreg is a major mechanism by which the thymus establishes dominant systemic tolerance throughout life. Our results further suggest that "tolerogenic" antigen-presenting cells (APCs) induce the formation of (THYreg) by selectively transporting antigens from the periphery to the thymus.

Goldschneider, I. (2006) Cyclical mobilization and gated importation of thymocyte progenitors in the adult mouse. Evidence for a thymus-bone marrow feedback loop. Immunol. Rev. 209:58-75.

Lai, L., R.A. Zeff, and Goldschneider, I. (2006) A recombinant single-chain
IL-7/HGFß hybrid cytokine induces juxtacrine interactions of the IL-7 and HGF (c-met) receptors and stimulates the proliferation of CFU-S12, common lymphoid progenitors (CLP) and pre-pro-B cells. Blood 107:1776-1784.

Donskoy, E. and Goldschneider, I. (2003) Two developmentally distinct populations of dendritic cells inhabit the adult mouse thymus. Demonstration by differential importation of hematogenous precursors under steady-state conditions. J. Immunol 170:3514-3521.

Goldschneider, I. and Cone, R. (2003) A central role for peripheral dendritic cells in the induction of acquired thymic tolerance. Trends Immunol. 24:77-81.

Donskoy, E. Foss, D. and Goldschneider, I. (2003) Gated importation of prothymocytes by adult mouse thymus is coordinated with their periodic mobilization from bone marrow. J. Immunol. 171:3568-3575.

Foss, D.L., Donskoy, E. and Goldschneider, I. (2001) The importation of hematogenous precursors by the thymus is a gated phenomenon in normal adult mice. J. Exp. Med. 183:365-373.

Wu, D.Y. and Goldschneider, I. (2001) Tolerance to cyclosporin-A-induced autologous graft-versus-host disease is mediated by a CD4+CD25+ subset of recent thymic emigrants. J. Immunol. 166:7158-7164.

Lai, L. and Golschneider, I. (2001) Cutting Edge: Identification of a hybrid cytokine consisting of Interleukin-7 and the b-chain of the Heptocyte Growth Factor/Scatter Factor. J. Immunol. 167:3550-3554.