of the Max - MDC

Structure of the Group
Group Leaders
Dr. Kirsten Falk
Dr. Olaf Rötzschke
Scientists
Dr. Mireille Starke
Dr. Markus Kleinewietfeld
Graduate and
Undergraduate Students
Fabiola Puentes
Sabine Höpner
Shashank Gupta
Katharina Dickhaut
Reiner Mailer
Alexander Sternjak
Jamina Eckhard*
Sebastian Günther*
Katja Müller*
Technical Assistants
Sabrina Kleißle
Jörg Contzen*
Anna-Maria Ströhl*
Secretariat
Sonja Giering
* part of the period reported
The impact of ‘MHC-loading enhancer’ (MLE)
on the immune response
Cooperation with the BMBF network project
‘MHCenhancer’ and the European MC-RTN ‘Drugs for
Therapy’
Another important aspect of the current research is antigen
processing and presentation. The peptide receptor displaying
the T cell antigens on the cell surface ere encoded by
the ‘Major Histocompatibility gene Complex’ (MHC). Class II
MHC molecules, the peptide receptors recognized by CD4+ T
cells, receive their antigens in an endosomal compartment.
In this compartment internalized proteins get degraded
into peptide fragments by proteases, which are than transferred
into the binding site of the MHC molecule by the
chaperone HLA-DM. Cell surface MHC molecules that have
lost their ligand rapidly inactivate by acquiring a ‘nonreceptive
state’. This safeguard mechanism prevents an
‘accidental’ exchange of peptide ligands by autoantigens
but also inhibits effective antigen-loading during peptide
vaccinations. In a recent project, however, the group discovered
that small molecular compounds can catalyze the
ligand-exchange of cell surface MHC molecules. Structural
and functional studies in cooperation with partners from
the ‘Leibnitz Institute of Molecular Pharmacology’ (FMP)
revealed that these ‘MHC-loading enhancer’ (MLE) target a
defined pocket of the class II MHC molecule. The transient
occupation of this pocket by the small molecule stabilizes
the peptide-receptive state in a similar way as the natural
catalyst HLA-DM. MLE compounds may therefore be useful
molecular tools to amplify immune responses during vaccination
or therapy. Another more basic questions related to
natural MLE-like compounds is their putative role in antigen
capture by dendritic cells. By triggering ‘uncontrolled’ ligand
exchange, they may represent risk factors for the induction
of allergies or autoimmune reactions. Both aspects are
currently being explored by the group in various animal
models.
Selected Publications
Piaggio, E, Mars, L T, Cassan, C, Cabarrocas, J, Hofstatter, M,
Desbois, S, Bergereau, E, Rotzschke, O, Falk, K, and Liblau, R S.
(2007). Multimerized T cell epitopes protect from experimental
autoimmune diabetes by inducing dominant tolerance. Proc
Natl Acad Sci U S A 104, 9393-9398.
Borsellino, G, Kleinewietfeld, M, Di Mitri, D, Sternjak, A,
Diamantini, A, Giometto, R, Höpner, S, Centonze, D, Bernardi,
G, Dell’Acqua, ML, Rossini, PM, Battistini, L, Rötzschke, O, Falk,
K. (2007). Expression of ectonucleotidase CD39 by Foxp3+ Treg
cells: hydrolysis of extracellular ATP and immune suppression.
Blood 110, 1225-32.
Höpner, S, Dickhaut, K, Hofstätter M, Krämer, H, Rückerl, D,
Söderhäll, JA, Gupta, S, Marin-Esteban, V, Kühne, R, Freund, C,
Jung, G, Falk, K, Rötzschke, O. (2006). Small organic compounds
enhance antigen loading of class II major histocompatibility
complex proteins by targeting the polymorphic P1 pocket.
J Biol Chem 281, 38535-38542.
Falk, K, Rotzschke, O, Stevanovic, S, Jung, G, and Rammensee,
HG (2006). Allele-specific motifs revealed by sequencing of selfpeptides
eluted from MHC molecules. 1991. J Immunol 177,
2741-2747.
Kleinewietfeld, M, Puentes, F, Borsellino, G, Battistini, L,
Rotzschke, O, and Falk, K. (2005). CCR6 expression defines
regulatory effector/memory-like cells within the CD25(+)CD4+
T-cell subset. Blood 105, 2877-2886.
Patent Applications
PCT/EP2005/010008 – „Änderung des Beladungszustands von
MHC Molekülen“
Invention disclosure (16.03.2007): “Use of repetitive regions of
parasite proteins fused to antigens to induce active and antigen
specific tolerance“
Invention disclosure (07.05.2007): “Use of peptide derivates as
MHC loading enhancers (MLE)”
142 Cancer Research