Preface - Ous-research.no

Transplantation and Malignancy
anti-cancer drugs, immunosuppressive drugs and small
molecular compounds (Src-, PI3-, MEK and p38-kinase
inhibitors) on TR cell function and effector T cell function.
Compounds with a preferential, different or selective effect
on either T cell subset, may point to important physiological
differences in the intracellular signal transduction machinery
with potential clinical value. Cell proliferation and
intracellular cytokine production will be assessed by flow
cytometry in CD4+ and CD8+ T cells.
1.3 The physiological role of regulatory T cells and the
mechanisms of action in interaction with effector T cells. In
this in vitro project, we will aim to elucidate the physiologic
role of regulatory T cells and the mechanisms of action in
interaction with effector T cells. Regulatory T cells have been
extensively studied for the last ten years. However, several
fundamental questions remain unanswered. The molecular
interactions underlying the immunosuppressive activity of
regulatory T cells are not known. Furthermore, the temporal
and cellular requirements of the immunosuppressive
activity of the regulatory T cells during the cell-cell interaction
with the effector T cells during an ongoing immune
response, have not been thoroughly dissected.
We have been addressing several basal l properties of Treg
function by seris of experiments studying the activation
Requirements and Kinetic Properties of Human Regulatory
T cells :
Naturally occurring regulatory T (TR) cells are crucial in
maintaining self tolerance by dominant suppression of
potentially self-reactive T cells in peripheral tissues. The
activation requirements, the temporal aspects of the suppressive
activity and mode of action of human naturally
occurring TR cells are subjects of great controversy. Ex vivo,
TR cells display great variability in the suppressive activity
dependent on donor and experimental conditions. Here
we show that by ex-vivo anti-CD3/anti-CD28 stimulation
and subsequent fixation in paraformaldehyde, TR cells
acquire full suppressive activity after 6 hours of stimulation.
However, the activation requirements are heterogenous as
70% of healthy blood donors have fully suppressive TR cells
without the need of ex-vivo stimulation. The suppressive
activity of TR cells operates in a contact-dependent manner
that is not dependent on dendrittic cells or other antigenpresenting
cells. The suppressive activity of paraformaldehyde
fixated TR cells can be fully obliterated by trypsin
treatment indicating that cytokine secretion is not required
for suppressive activity, but that a cell-surface protein is
directly involved. By using inhibitors for downstream signaling
pathways involved in T cell activation, we were not able
to inhibit the upregulation of TR cell mediated suppressive
activity, indicating that this mechanism may be dependent
on several pathways that operate in concert.
These findings establishes a method for further studying a
core suppressive mechanism in TR cells wich in turn could
lead to therapeutically exploitable targets.
Main Collaborators and Participating Institutions
Karl Erik Giercksky, Prof, MD, PhD, Surgical Oncology
Kjetil Taskén, Prof, MD, PhD, The Biotechnology Centre of
Oslo
Gustav Gaudernack, Prof. MSc, PhD, Clinical Gene Therapy
and Research
Bjørn Naume Prof, MD, PhD, Dep. of Oncology
Kirsten Muri Boberg, MD, PhD, Dep. of Internal Medicine
Ivar P. Gladhaug Prof, MD, PhD, Division of Surgery
Øystein Mathisen MD, PhD, Division of Surgery
Stein Bergan, Prof, MSc, PhD, Dep. of Clinical Pharmacology
Øystein Fodstad, Prof, MD, PhD, Dep. of Tumor Biology
Gunhild M. Mælandsmo, Prof MD, PhD, Dep. of Tumor
Biology
Per O. Seglen, Prof, MD, PhD. Dep. of Cell Biology, Proteomics
& Mammalian Cell Biology
Jahn M Nesland, Prof., M.D., Ph.D. Micrometastasis Laboratory
Gunnar Kvalheim, Prof, MD, PhD, Clinical Stem Cell Laboratory
Halvdan Sørbye, Prof, MD, PhD Dep. of Oncology, UiB
International Collaborators
Professor Olle Korsgren, MD, PhD, Department of Immunology,
Uppsala University Hospital, S.
Professor Bo-Göran Ericzon, MD, PhD, Head of division
Transplantation Surgery, Center for Surgical Sciences, Karolinska
Institutet, StockholmUniversity, S.
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