ICI 2016_Abstract Book

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International Congress of Immunology 2016 Abstract Book
Treg 1
2600
Nr4a receptors promote completion of Treg cell
developmental program and prevent conversion of labile
Treg precursors into pathogenic cells
Sekiya, T., Yoshimura, A.
Keio University School of Medicine, Department of Microbiology
and Immunology, Tokyo, Japan
Recently, our group reported that Nr4a family of nuclear orphan
receptors plays crucial roles in Treg cell development. In this
study, we investigated molecular mechanisms for Treg cell
development in the thymus, by focusing on the roles mediated
by Nr4a. First, we tried to distinguish Nr4a-dependent and
-independent Treg cell developmental programs. As a result,
we found that several Treg cell-developmental programs were
strictly dependent on Nr4a, including suppression of majority
of inflammatory cytokine genes, and induction of Ikzf4 (Eos). On
the other hand, induction of many genes in the Treg-signature
gene set, including Ctla4 and Il2ra, were revealed to be
independent of Nr4a function. Even Foxp3 was induced, albeit at
a reduced level, in Nr4a-defficient Treg precursor (preTreg) cells.
However, the Foxp3 expression in Nr4a-defficient preTreg cells
was so transient and unstable, that the expression disappeared
within one day, even under a supporting condition for Foxp3
expression. Next, we analyzed cooperation between Nr4a and
other Treg-developmental factors, including IL-2/CD25 and TNF
superfamily (TNFSF)/TNF receptor super family (TNFRSF). By
an in vitro system, we revealed that Nr4a were indispensable
for IL2/CD25- and TNFSF/TNFRSF-mediated conversion of Treg
precursor into Tregs. On the other hand, it was also suggested
that Nr4a alone could not induceTregs, but requires cooperation
with IL2/CD25 and TNFSF/TNFRSF. Finally, we found that Nr4a-
deficient preTreg cells have a potential to induce autoimmunity.
Reflecting the diverse spectrum of self-reactive TCR repertoire
of Tregs, Nr4a-deficient preTreg cells elicited autoimmunity
against diverse array of self-antigens, including both ubiquitous
and tissue-specific ones.
3469
Human Foxp3-negative follicular regulatory T cells control
IgE responses
Canete, P.F.1 , Sweet, R.A.1, Papa, I. 1, Gonzalez-Figueroa, P.1, Ohkura,
N.2, Cuenca, M.1, Silva-Cayetano, A.1, Ohms, S.J.3, Barry, E.4,
Grimbaldeston, M.5, Sakaguchi, S.2, Cook, M.C.1,6, Vinuesa, C.G.1
1JCSMR/Australian National University, Immunology and Infectious
Disease, Canberra, Australia, 2WPI Immunology Frontier Research
Center, Osaka University, Laboratory of Experimental Immunology,
Osaka, Japan,3JCSMR/Australian National University, ACRF
Biomolecular Resource Facility, Canberra, Australia,4Centre for
Cancer Biology, University of South Australia & SA Pathology,
Cytokine Receptor Laboratory, Adelaide, Australia, 5Centre for
Cancer Biology, University of South Australia & SA Pathology,
Mast Cell Laboratory, Adelaide, Australia, 6Canberra Hospital,
Translational Research Unit, Canberra, Australia
Antibody responses to most infectious and food protein
antigens depend on help to B cells from specialised T follicular
helper (Tfh) cells. A subset of Foxp3+ regulatory T cells (Tregs)
has been described in mice, with a prominent role in repressing
germinal center reactions that are critical for memory B cell
formation and long-lived antibody responses. These specialised
Tregs co-opt the Bcl-6-dependent Tfh differentiation pathway in
order to access the B cell-rich follicles and have therefore been
designated as T follicular regulatory (Tfr) cells. Little is known
about the ontogeny or function of human Tfr cells. Here we
identify a unique Bcl-6-expressing follicular regulatory T cell in
human secondary lymphoid tissue, that lacks Foxp3 expression
and the thymic-imprinted Foxp3 methylation pattern, but
shares expression of key Treg molecules. These cells, designated
Tfr2 cells, are the predominant source of T cell-derived IL-10
in human tonsil. Whereas IL-10 alone promotes B cell terminal
differentiation into plasma cells, IL-10-producing Tfr2 cells
suppress human B cell differentiation and profoundly limit IgE
production. Intriguingly, Tfr2 cells only exert their effects in
the presence of Tfr2 cells, at least in part through repressing
Tfh-derived IL-21 and CD40L. Tfr2 cells are enriched at human
oral-associated lymphoid tissues; continuous exposure to food
antigens at these sites make Tfr2 cells an ideal candidate to
suppress food allergies.
3642
Selective control of regulatory T cells through TCR signaling
molecule
Tanaka, A.1, Nishikawa, H.1, Noguchi, S.1,2, Morikawa, H.1,
Takahashi, N.2, Sakaguchi, N.1, Sakaguchi, S. 1
1 Osaka University, Immunology Frontier Research Center, Suita,
Japan, 2Akita University, Department of Hematology, Nephrology,
and Rheumatology, Akita, Japan
Regulatory T (Treg) cells are essential for the active maintenance
of immunological self-tolerance and homeostasis. On the other
hand, Treg cells infiltrate tumors and hinder effective anti-tumor
immune responses in patients, requiring a method to selectively
control Treg cells in tumors without eliciting autoimmunity.
Here we show that in Treg cells, proximal TCR signaling
molecules including Lck and ZAP-70 are regulated specifically
to maintain low levels of gene expression and/or basal kinase
activity. This Treg-specific repression renders Tregs, especially
terminally differentiated and highly suppressive Foxp3 + effector
Treg (eTreg) cells, vulnerable to inhibition of Lck and leads to
selective depletion of eTreg cells in humans. Imatinib, a tyrosine
kinase inhibitor of the oncogenic BCR-ABL fusion protein
specifically expressed in chronic myelogenous leukemia (CML)
cells, inhibits tyrosine phosphorylation of Lck, as an off-target
effect. Long-term imatinib-treated CML patients in complete
molecular remission showed selective depletion of eTreg
cells whereas those failed in molecular remission did not. The
former concurrently exhibited a general increase in the number
of effector- or memory-type CD8 + T cells producing multiple
cytokines. In vitro, imatinib induced apoptosis predominantly
in eTreg cells, augmenting CD8 + T-cell responses against various
tumor antigens in healthy individuals and cancer patients.
Imatinib is, therefore, able to attenuate TCR signaling intensity
more profoundly in eTreg cells than in other T cells, rendering