Oral Presentations - Federation of Clinical Immunology Societies

S6 Abstracts
OR.6 Islet Antigen Specific Regulatory T Cells
Isolated From Non-Diabetic Individuals Suppress
Pro-Inflammatory Responses via Cytotoxic Mechanisms
Timothy Tree, Lecturer, Department of Immunobiology,
King’s College London, London, Jenifer Lawson, Research
Assistant, Department of Immunobiology, King’s College
London, London, Bart Roep, Professor, Department of
Immunohaematology and Blood Transfusion, Leiden
University Medical Center, Leiden, Hannah Edwards,
Research Technician, Department of Immunobiology,
King’s College London, London, England, Mark Peakman,
Professor of Clinical Immunology, Department of
Immunobiology, King’s College London, London,
England
Autoreactive T cells recognizing islet ? cell antigens
could represent both pathogenic effectors in the development
of type 1 diabetes (T1DM) and mediators of
tolerance in non-diabetic individuals depending on the
quality of response they produce. We have previously
demonstrated that, whereas autoreactive T cells in
patients with T1DM exhibit polarization towards a proinflammatory
T helper 1 (Th1) phenotype, the majority of
non-diabetic subjects also manifest a response against
islet peptides, but one that shows T regulatory cell (Treg),
IL-10 secreting, bias. We therefore proposed that isletspecific
IL-10 producing T cells may be involved in the
maintenance of tolerance to islets by the suppression of
proinflammatory Th1 cells. To test this hypothosis, we
isolated T cell clones from healthy individuals that secrete
high levels of IL-10 in response to islet antigens directly
ex vivo. These CD4+CD25+Foxp3+ Tregs are potent
suppressors of proinflammatory Th1 effector cells. Suppression
is not mediated by soluble factors but is cellcontact
dependent, and dependent upon presentation of
stimulating antigens for both the Treg and effector Th1
cells by the same antigen presenting cell (APC), thus
providing exquisite specificity of suppression. These Tregs
express the cytotoxic molecules perforin and granzymes A
and B directly ex vivo and mediate their suppression via
the specific lysis of APC presenting high levels of islet
antigens. This hitherto un-described population of antigen
specific Tregs, which appear to be constitutively present
in the majority of non-diabetic individuals, may provide a
suitable target to strengthen tolerance to islets by clinical
immunointervention.
doi:10.1016/j.clim.2007.03.187
OR.7 Rapamycin Promotes Induction of CD4+Foxp3+
T Cells that Proliferate in Response to Common
Gamma Chain Cytokines
S. Alice Long, Scientist, Benaroya Research Institute,
Seattle, WA, Megan Van Landeghen, RA II, Benaroya
Research Institute, Seattle, WA, Jane Buckner, Professor,
Benaroya Research Institute, Seattle, WA
We and others have shown that CD4+CD25+Foxp3+ T
cells can be induced from CD4+CD25−Foxp3− T cells
(iTReg). Using intracellular staining for Foxp3, we consistently
observe that the CD4+CD25+ population that arises
upon activation of CD4+CD25− T cells with polyclonal or
antigenic stimulation is composed of both Foxp3− and Foxp3+
T cells. Thus, determining factors that influence the
frequency of iTReg may lead to development of targeted
therapies. IL-2 is a known growth factor for natural Treg.
Others have observed that treatment of patients with
Rapamycin leads to an increased number of CD4+CD25+
Foxp3+ Tcells. Here, we demonstrate that in vitro activation
of CD4+CD25− T cells in the presence of IL-2 or Rapamycin
results in generation of functional iTReg. However, combination
of both Rapamycin and IL-2 results in a significantly
higher frequency and absolute number of iTReg. Analysis of
Foxp3 over time demonstrates that up-regulation of Foxp3
occurs prior to cell division and increases during the course
of cell division. Foxp3− and Foxp3+ T cells proliferate in
parallel suggesting that Rapamycin is not significantly
inhibiting the proliferation of Foxp3− T cells, but instead,
is preferentially inducing Foxp3 expression in a subset of
CD25− T cells. The addition of IL-2, but also IL-4, IL-7, and
IL-15, facilitates proliferation of iTReg. Thus, we demonstrate
that Rapamycin plus IL-2 and/or common gamma
chain cytokines promotes induction and proliferation of
Foxp3+ T cells. These studies provide rationale for using
Rapamycin in combination with IL-2 to enhance expansion
of regulatory T cells in vivo.
doi:10.1016/j.clim.2007.03.188
OR.8 IL-2Rβ Links IL-2R Signaling with Foxp3
Expression
David Soper, Graduate Student, University of Washington,
Department of Immunology, Seattle, WA
Immunological tolerance to self-antigens is a tightly
regulated process. Recent work has demonstrated that
the forkhead family member Foxp3 is a critical element in
the differentiation and function of mouse CD4+CD25+
regulatory T (TR) cells. Recent work has suggested an
important role for IL-2 in the development and maintenance
of TR cells. To directly assess the effect of IL-2
signaling on TR development and function, we analyzed
mice that were genetically deficient in components of the
IL-2 receptor (IL-2R). Mice lacking CD25 (IL-2Rα) displayed
a slight decrease in TR cells within the thymus, while
peripheral numbers are unchanged. In contrast, we found
that mice deficient in CD122 (IL-2Rβ) had a profound
reduction in both thymic and peripheral TR cells,
coinciding with more rapid development of a fatal
lymphoproliferative disease. Expression of a Foxp3 transgene
restored TR cells and protected against the onset of
autoimmunity. Thus, a signal mediated by IL-2Rβ is essential
for the development and homeostasis of Foxp3+ TR cells
in vivo.
doi:10.1016/j.clim.2007.03.189