Areas of Interest
1. Development of T Lymphocytes.
Despite information about maturational events amongst
thymocytes, substantial controversy remains about the origins,
function, and fate of recent thymic emigrants (RTE’s) and
prothymocytes. 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 prothymocytes 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 hybrid cytokine
comprised of Interleukin (IL)-7 and the β-chain of hepatocyte
growth factor (HGFβ) in the regulation of common lymphoid
progenitors and pre-pro-B cell growth and differentiation.
Studies are in progress using IL-7 gene-deleted mice, to
determine the mechanism of action of this novel growth factor.
Our recent results indicated that the IL-7/HGFβ 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 RTEreg have a abTCR+ CD4+
CD25+ phenotype and others a TCR+ 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.
Publications
Selected Publications
*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/HGFβ 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.
Wei, C. Lai, L. and *Goldschneider, I. (2002) Pre-pro-B cell
chaingrowth-stimulating factor (PPBSF) upregulates the
expression of the IL-7R and enables pro-B cells to respond to
monomeric IL-7. J. Interferon Cytokine Res. 22:823-832.
Foss, D.L., Donskoy E. and *Goldschneider, I. (2002)
Functional demonstration of intrathymic binding sites and
microvascular gates for prothymocytes in irradiated mice. Int.
Immunol. 14:331-338.
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 subset of recentCD25autologous
graft-versus-host disease is mediated by a CD4 thymic emigrants.
J. Immunol. 166:7158-7164.
Lai, L. and *Golschneider, I. (2001) Cutting Edge:
Identification of a hybrid -chain of the Heptocyte
Growthcytokine consisting of Interleukin-7 and the
Factor/Scatter Factor. J. Immunol. 167:3550-3554.
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