Researchers have demonstrated a new activity of an intracellular enzyme
in the generation of an HIV epitope (an epitope is a good target for the
lymphocytes stimulated by vaccines). What is original with this finding
is that it unseats the proteasome, the intracellular enzymatic complex
which, until now, seemed irreplaceable to make one of the enzymatic cuts
producing these epitopes. The team of the Cochin Institute(1)
directed by CNRS researcher Anne Hosmalin conducted this research as part
of an international collaboration. Their findings, which were published
in the April 2003 issue of the journal Nature Immunology(2),
may have an impact on the development of new generation vaccines against
viruses and tumors.
Lymphocytes in the immune system know how to recognize viral proteins
and cancer cells in order to prevent their proliferation. Vaccination,
whether preventive or therapeutic, stimulates the responses of these lymphocytes.
New generation vaccines contain epitopes, fragments of viral proteins
or tumors that are recognized by T lymphocytes. Such fragments are not
infectious. When CD8 T lymphocytes recognize the epitopes, they destroy
the infected or cancerous cells by producing anti-viral or anti-cancer
factors, such as gamma interferon.
Understanding the mechanisms involved in the generation of epitopes makes
it possible to characterize the epitopes that are useful for the activation
of T lymphocytes in the composition of vaccines. For the scientists, an
intracellular enzyme appeared to be required to generatef CD8 T cell epitopes:
the proteasome. Their research demonstrated an example where the activity
of the proteasome is replaced by that of another intracellular enzyme
called TPP II (Tripeptidyl peptidase two). If confirmed for other epitopes,
the new role of TPP II should be taken into account for the development
of new generation vaccines against viruses and tumors.
These findings were obtained using human dendritic(3)
cells and a dominant HIV epitope contained in the Nef protein that is
recognized by CD8 lymphocytes. The Nef protein is a good target for vaccination
against HIV, as it is expressed early in the viral cycle. Following digestion
by the cell into peptides, the epitopes of this protein can be recognized
by CD8+ T lymphocytes before the virus produces structural proteins. Thus,
infected cells can be destroyed and viral replication can be inhibited
before viruses are produced. .
An essential role for tripeptidyl peptidase in the generation of an MHC
class I epitope, Nature Immunology, April 2003.
Ulrike Seifert (1), Concepción Marañón (2), Ayelet
Shmueli(3), Jean-François Desoutter (2), Lisa Wesoloski(1), Katharina
Janek(1), Peter Henklein (1), Susanne Diescher (4), Muriel Andrieu (2),
Henri de la Salle (5), Toni Weinschenk (6), Hansjörg Schild (6),
Diego Laderach (7), Anne Galy (7), Gaby Haas (4), Peter-M. Kloetzel(1),
Yuval Reiss (3) et Anne Hosmalin (2).
(1) Institut für Biochemie-Charité, Medical Faculty of the
Humboldt-University Berlin, Berlin, Germany;
(2) Institut Cochin, Département d´Immunologie, U Inserm
567, CNRS UMR 8104, IFR Alfred Jost, Paris, France;
(3) Department of Biochemistry, George S. Wise Faculty of Life Sciences,
Tel Aviv University, Tel Aviv, Israel;
(4) Max Planck Institut für Infektionsbiologie, Department of Molecular
Biology, Berlin, Germany;
(5) INSERM EP99-08, EFS-Alsace, 676065 Strasbourg, France;
(6) Institute for Cell Biology, Department of Immunology, University of
Tübingen, Tübingen, Germany;
(7) INSERM U362, Institut Gustave Roussy, Villejuif and Généthon,
(1) The Cochin Institute is a research unit run jointly
by the CNRS (UMR 8104), the INSERM (U567) and the Université René
Descartes Paris 5 (IFR Alfred Jost).
(2) The article was posted on line February 24, 2003 at:
(3) Dendritic cells play a very important role in the
immune system: by presenting epitopes to T lymphocytes, they stimulate
T lymphocyte immune responses.
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