ICI 2016_Abstract Book
Previous Page  4 / 827 Next Page
Information
Show Menu
Previous Page 4 / 827 Next Page
Page Background

4

International Congress of Immunology 2016

Abstract Book

Oral Abstract Sessions

10:30 - 12:10

Transcription Factors

2131

The dual role of Bcl6 in the regulation of the differentiation

and function of follicular cytotoxic T cells

Chen, Y.

1

, Leong, Y.A.

1

, Man, K.

2

, Ong, H.

1

, Wu, D.

3

, Kallies, A.

2

, Yu, D.

1

1

Monash University, Department of Biochemistry and Molecular

Biology, Melbourne, Australia,

2

Walter and Eliza Hall Institute

of Medical Research, Melbourne, Australia,

3

University of North

Carolina, Chapel Hill, United States

Follicular helper T (Tfh) cells are a subset of CD4+ helper T

cells that express the chemokine receptor CXCR5 and migrate

into B-cell follicles. Tfh cells support germinal centre response

for antibody affinity maturation and memory formation. As

the master transcription factor for Tfh differentiation, Bcl6 is

required for CXCR5 expression on CD4+ T cells. Recently, my

lab identified a subset of CD8+ cytotoxic T cells that express

CXCR5 and localize to B-cell follicles in a model of viral infection.

CXCR5+ CD8+ T cells are required to control the infection of Tfh

cells and termed follicular cytotoxic T (Tfc) cells. As in Tfh cells,

we found Bcl6 was also upregulated in Tfc cells. The loss of Bcl6

led to the defects of Tfc differentiation while overexpression of

Bcl6 promoted the differentiation of Tfc cells. Importantly, we

also found Bcl6 suppresses the cytotoxic function by inhibiting

the expression of genes that encode cytotoxic molecules

such as Granzyme B. In HIV infections, Tfh cells serve as the

major CD4 T cell compartment for HIV-1 infection, replication,

and production. The discovery of the dual role of Bcl6 in the

regulation of Tfc differentiation and function might provide an

explanation why CD8+ T cells are less effective to control the

infection of Tfh cells in B-cell follicles than non-Tfh cells in T-cell

zone.

2075

Mapping regulatory networks in human regulatory T cells

by chromatin conformation capture

Sadlon, T.

1,2

, Bandara, V.

1

, Brown, C.

1

, Beyer, M.

3

, Schultze, J.

3

, Bent,

S.

1

, Forrest, A.

4

, Barry, S.

2

1

Molecular Immunology, Robinson Research Institute,

Adelaide, Australia,

2

Women’s and Children’s Health Network,

Gastroenterology, Adelaide, Australia,

3

LIMES, University of Bonn,

Bonn, Germany,

4

Henry Perkins Insitute for Medical Research,

Gemomics, Perth, Australia

Regulatory T cells (Treg) play a key role in tolerance and

immune homeostasis. Our research has revealed that Treg

function and stability is orchestrated by gene networks

regulated by FOXP3 and microRNAs. It is now evident that

coordinated gene regulation occurs in a cell specific manner

to bring together regulatory elements and coding regions,

and this is conformation dependant. While bioinformatics can

predict targets of transcription factors with some accuracy,

and genomics datasets can now identify functional motifs in

chromatin, such as super enhancers and lncRNAs, the targets

of these regions cannot be predicted by linear annotation

models. Conformation capture can determine which non

coding elements interact with Treg specific genes, and we can

superimposeonthisourFOXP3bindingsitedata.Thisanalysiswill

reveal the conformation dependant transcriptional regulation

of Treg genes, and will also allow for the first time annotation of

SNPs from autoimmune diseases to functional targets. As proof

of principle we have used SATB1, a key FOXP3 repressed gene in

Treg (1), as a conformation capture target. Using 4Cseq we have

identified a T cell specific activation induced FOXP3 responsive

super enhancer over 300Kb upstream, and this region includes

5 enhancer elements. We now confirm that this enhancer is T

cell activation dependant, is repressed by FOXP3, and overlaps a

number of IBD/Colitis SNPs from GWAS datasets, confirming the

power of this approach. The functional impact of autoimmune

SNPs on SATB1 expression is now under investigation

1) Beyer M, et al. Nature immunology 2011;12(9):898-907.

768

A combinatorial threshold model for effector differentiation

of CD8

+

T cells mediated by Blimp-1 and T-bet

Masson, F.

1,2,3

, Xin, A.

2,3

, Liao, Y.

2,3

, Preston, S.

2,3

, Guan, T.

4

, Gloury,

R.

2,3

, Olshansky, M.

2,5

, Lin, J.-X.

6

, Li, P.

6

, Speed, T.P.

2,7

, Smyth, G.K.

2,7

,

Ernst, M.

1,8

, Leonard, W.J.

6

, Pellegrini, M.

2,3

, Kaech, S.

4,9

, Nutt, S.L.

2,3

,

Shi, W.

2,7

, Belz, G.T.

2,3

, Kallies, A.

2,3

1

Olivia Newton-Jonh Cancer Research Institute, Cancer

Inflammation Laboratory, Heidelberg, Australia,

2

Walter & Eliza

Hall Institute, Parkville, Australia,

3

University of Melbourne,

Department of Medical Biology, Parkville, Australia,

4

Yale University

School of Medicine, Department of Immunobiology, New Haven,

United States,

5

University of Melbourne, Department of Computing

and Information Systems, Parkville, Australia,

6

National Heart,

Lung and Blood Insitute, NIH, Bethesda, United States,

7

University

of Melbourne, Department of Mathematics and Statistics, Parkville,

Australia,

8

La Trobe University, School of Cancer Medicine,

Heidelberg, Australia,

9

Howard Hughes Medical Institute, Chavy

Chase, United States

T cell responses are guided by cytokines that induce

transcriptional regulators, which ultimately control the

differentiation of effector and memory T cells. However,

it is unknown how their activities are coordinated and

integrated during this process. In the present study, we used

broad transcriptional profiling of antigen-specific CD8

+

T

cells to systematically dissect the relative contributions and

interdependency of two major drivers of CD8

+

effector T cell

differentiation, Blimp-1 and T-bet. Furthermore, we unraveled

how IL-2 impacts on transcriptional changes during effector

cell differentiation

in vivo

. We showed that Blimp-1 acts as

a signal integration node for IL-2 and pro-inflammatory

cytokines, in particular IL-12, which overlap to initiate effector

differentiation. Moreover, while deficiency in either Blimp-1 or

T-bet left effector function partially intact, combined ablation of

both factors resulted in loss of expression of effector molecules

and an inability to control systemic viral infection. Importantly,