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International Congress of Immunology 2016

Abstract Book

the former more susceptible to signal-deprived apoptotic cell

death. Thus, small molecules that can selectively deplete eTreg

cells via exploiting Treg-specific functions are instrumental in

augmenting anti-tumor immunity in various cancers.


Pharmacological inhibition of acid sphingomyelinase or

genetic ablation enhances CD4




regulatory T cell


Hollmann, C.


, Reuter, D.


, Werner, S.


, Avota, E.


, Müller, N.


, Japtok,



, Kleuser, B.


, Becker, K.A.


, Gulbins, E.


, Schneider-Schaulies, J.



Beyersdorf, N.



University of Wuerzburg, Institute for Virology and

Immunobiology, Wuerzburg, Germany,


University of Potsdam,

Institute of Nutritional Science, Nuthetal, Germany,


University of

Duisburg-Essen, Institute for Molecular Biology, Essen, Germany

The acid sphingomyelinase (human: ASM, mouse: Asm)

hydrolyses sphingomyelin into phosphocholine and ceramide

which generates signalling platforms and affects viral

pathogenicity. CD4




regulatory T (Treg) cells depend on

CD28 signalling for their survival and function, a receptor that

has previously been shown to activate the Asm/ASM. In line

with these findings we observed that Treg cells of wild-type (wt)

mice displayed higher basal and CD28-induced Asm activity

and, thus, contained more ceramide than conventional CD4



(Tconv) cells. Investigating Asm-deficient mice we could show

that the frequency of Treg cells among CD4


T cells is increased

and their suppressive activity is enhanced compared to wt

mice - at least partially due to a higher turnover of the effector

molecule CTLA-4. Similar to anti-CD28 antibody-mediated

expansion of Treg cells in wt mice, these changes in Treg cell

frequencies and/ or function in the Asm-deficient mice were

associated with more infected neurons using a CNS infection

model with recombinant measles virus. Of clinical importance,

pharmacological inhibition of Asm in mouse splenocytes

in vitro

and in mice

in vivo

led to higher frequencies of Treg cells among



T cells, as did ASM inhibition in primary human peripheral

blood mononuclear cells (PBMC). ASM inhibitors should, thus,

be considered as potential immunomodulatory agents for the

therapy of inflammatory and autoimmune disorders. This study

was supported by a grant from the DFG (FOR2123/P02).


TCR signal strength regulates Akt substrate specificity to

induce alternate Th and Treg differentiation programs

Morel, P.A.


, Hawse, W.F.


, Sheehan, R.P.


, Boggess, W.C.


, Faeder,




University of Pittsburgh, Immunology, Pittsburgh, United States,


University of Pittsburgh, Computational and Sysems Biology,

Pittsburgh, United States,


UnIversity of Notre Dame, Notre Dame,

United States

T regulatory (Treg) cells are induced following stimulation of

naïve CD4 T cells with low dose antigen to an extent that is

negatively correlated with signaling via the Akt/mTOR pathway.

Strong TCR signals induce high levels of Akt activity that inhibit

development of Treg by poorly understood mechanisms. Here,

we show that high dose stimulation of T cells results in the

phosphorylationof Akt on two regulatory sites, Serine (S) 473and

Threonine (T) 308, whereas low dose stimulation results in only

T308 phosphorylation. Mathematical modeling shows that the

dual phosphorylation of Akt on S473 and T308 is controlled by

a feedback loop involving PTEN, mTORC2 and the transcription

factor FoxO1 that creates a sharp activation threshold with

respect to antigen dose and stimulus duration. Using mass

spectrometry to analyze phosphorylated Akt substrates at

different levels of stimulation, we find profound differences

in the substrates phosphorylated, suggesting that a switch in

substrate specificity coupled to the phosphorylation status

of Akt may lead to alternative cell fates. Proteins differentially

phosphorylated by these two states of Akt include RNA splicing

factors, and we find changes in the splice variant expression

levels of key TCR signaling proteins, such as CD3ζ and CD45 that

correlate with the observed differences in cell fate. Knockdown

of specific splicing factors changed the ratios of Th versus Treg

cells induced. Together, this work demonstrates that alternative

splicing can affect the outcome of T cell fate decisions and

identifies alternate Akt-mediated signaling networks that drive



T cell differentiation.


Evaluation of Galectin-9 blocking mono-clonal antibodies

as novel immune-checkpoint inhibitors via the targeting of

regulatory T cells in cancer

Mustapha, R.


, Mrizak, D.


, Renaud, S.


, Barjeon, C.


, de Launoit, Y.



Pancré, V.


, Moralès, O.


, Busson, P.


, Delhem, N.



CNRS, UMR 8161, Institut de Biologie de Lille, Lille, France,


Université Paris-sud, CNRS UMR 8126 and Institut Gustave Roussy,

Villejuif, France

The immune system has the potential to recognize and

eliminate cancer cells but is held back by certain inhibitory

pathways. Regulatory T cells (Tregs) are key players in these

pathways. They are a subpopulation of T lymphocytes whose

role is to inhibit the immune response in order to maintain

immunological homeostasis. However, the Treg population is

often upregulated in cancer patients where it promotes tumor.

This has made Tregs an appealing target for immunotherapeutic

approaches such as anti-CTLA-4 and anti-PD-1. Galectin-9

(Gal-9) a b-galactoside binding lectin has been described as

an immunosuppressive molecule which is expressed by both

cancer cells and Tregs in order to suppress the anti-tumoral

immune response. In this study we first aimed to confirm the role

of Gal-9 in Treg-mediated-immuno-suppression. Then we tested

the effects of Gal-9 blocking on Treg function and subsequently

the anti-tumoral immune response. Following Treg isolation

from healthy donors, we have proven via QPCR, ELISA and

flow cytometry that Gal-9 is highly expressed and secreted by

Tregs with respect to conventional T cells. Moreover, the anti-

Gal-9 antibody significantly inhibited the immuno-suppressive

function of Tregs in mixed leukocyte reaction proliferation tests.

We have also demonstrated that Gal-9 blocking in PBMC culture

promotes the secretion of Th1 cytokines TNF-a and IFN-g.

Finally, we successfully used the anti-Gal-9 antibody to inhibit