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International Congress of Immunology 2016

Abstract Book

Treg 1


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


(Eos). On

the other hand, induction of many genes in the Treg-signature

gene set, including




, 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.


Human Foxp3-negative follicular regulatory T cells control

IgE responses

Canete, P.F.


, Sweet, R.A.


, Papa, I.


, Gonzalez-Figueroa, P.


, Ohkura,



, Cuenca, M.


, Silva-Cayetano, A.


, Ohms, S.J.


, Barry, E.



Grimbaldeston, M.


, Sakaguchi, S.


, Cook, M.C.


, Vinuesa, C.G.



JCSMR/Australian National University, Immunology and Infectious

Disease, Canberra, Australia,


WPI Immunology Frontier Research

Center, Osaka University, Laboratory of Experimental Immunology,

Osaka, Japan,


JCSMR/Australian National University, ACRF

Biomolecular Resource Facility, Canberra, Australia,


Centre for

Cancer Biology, University of South Australia & SA Pathology,

Cytokine Receptor Laboratory, Adelaide, Australia,


Centre for

Cancer Biology, University of South Australia & SA Pathology,

Mast Cell Laboratory, Adelaide, Australia,


Canberra 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.


Selective control of regulatory T cells through TCR signaling


Tanaka, A.


, Nishikawa, H.


, Noguchi, S.


, Morikawa, H.



Takahashi, N.


, Sakaguchi, N.


, Sakaguchi, S.



Osaka University, Immunology Frontier Research Center, Suita,



Akita 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



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