July 6, 2005
Notch Protein Signaling Directs
Early T-Cell Development
A Better Grasp of Immune Cell Lineages
May Improve Outcomes for Transplant,
Other Immunosuppressed Patients
(Philadelphia, PA) - Researchers at the University
of Pennsylvania School of Medicine have recently
clarified the role of the Notch protein in T-cell development.
T cells are required for many aspects of immunity, including
fighting viral infections, providing cancer surveillance,
and regulating multiple aspects of the immune response.
T cells are made in the thymus, a small organ situated
under the breastbone near the heart, whose primary function
is T-cell production. However, T cells ultimately come
from hematopoietic (blood-producing) stem cells in the
bone marrow, from which all blood-cell types begin.
A progenitor cell leaves the bone marrow to seed the
thymus, eventually giving rise to T cells. In the absence
of instructions by the Notch protein, T-cell development
does not occur, even in the presence of a normal thymus.
In this study — published in the most recent issue
of Nature Immunology — the investigators
found that Notch, a protein that regulates diverse cell-fate
decisions in multi-cellular organisms, is active in
very early T-cell progenitors in the thymus of mice.
Notch contributes to the subsequent differentiation
of these early T-cell progenitors into T cells.
“Notch signaling instructs multi-potent progenitor
cell types to enter the T-cell developmental pathway,”
says senior author Avinash Bhandoola, MD, PhD,
Assistant Professor of Pathology and Laboratory Medicine.
“However, we don’t yet understand in which
tissue these instructions are being delivered, and which
cell type is the recipient.”
Co-author Warren Pear, MD, PhD, Associate
Professor of Pathology and Lab Medicine and member of
Penn’s Abramson Family Cancer Research
Institute and Institute for Medicine
and Engineering, was one of the original discoverers
of the role of Notch in T-cell development. His lab
developed tools to block Notch signaling, which were
key to identifying its function in T-cell progenitors.
Findings from this current study suggest that Notch
acts very early after progenitor cells enter the thymus,
among other probable points in T-cell development.
Notch activates gene transcription in the nucleus of
cells, and depending on the biochemical context, it
turns certain pathways on, and others off. “To
the extent that we know where, and in which cells Notch
is acting, we may be able to figure out how Notch works
in the thymus,” says co-lead author Arivazhagan
Sambandam, PhD, Research Associate, also in
the Department of Pathology and Laboratory Medicine.
“Studying events in the thymus is important because
intrathymic events may be a bottleneck in T-cell reconstitution,
which is deficient in post-transplant patients,”
says co-lead author Ivan Maillard, MD, PhD,
Research Associate in the Division of Hematology-Oncology
and the Abramson Family Cancer Research Institute. “What
the study allows us to do is begin to define exactly
where intrathymic Notch signaling happens and where
to look for problems and for the relevant molecular
In many clinical situations, early T-cell progenitors
are likely to be deficient-especially in patients undergoing
bone marrow or hematopoietic stem cell transplantation,
in whom new T cells fail to be produced for long periods
of time. In some, especially elderly patients, there
is never true recovery of T cells, and such non-recovery
is associated with problems such as infections. To improve
the outcome of transplant patients, the process of T-cell
development needs to be better understood. This may
also be important in cancer patients who get profound
immunosuppression from treatments and in AIDS patients
when T cells are not made at a sufficient rate to replenish
the T-cell pool.
The Pear and Bhandoola labs plan to apply the knowledge
gained in their basic scientific studies to the clinic.
According to Maillard, “In humans, it’s
more difficult to look inside the thymus, but we plan
to use our unique Notch reagents in model systems to
generate hypotheses about the exact nature of Notch
control of T-cell development, eventually moving that
knowledge to relevant clinical situations.”
Other Penn co-authors are Valerie P. Zediak, and Lanwei
Xu. Co-authors at other institutions are Rachel M. Gerstein
from the University of Massachusetts Medical School
and Jon C. Aster, from Brigham and Women’s Hospital,
Boston. Funding for the study was provided by the National
Institutes of Health, the Damon Runyon Cancer Research
Foundation, the Leukemia and Lymphoma Society, the Commonwealth
of Pennsylvania, and the Swiss Society for Grants in
Medicine and Biology.
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