International Congress of Immunology 2016
Oral Abstract Sessions
10:30 - 12:10
The dual role of Bcl6 in the regulation of the differentiation
and function of follicular cytotoxic T cells
, Leong, Y.A.
, Man, K.
, Ong, H.
, Wu, D.
, Kallies, A.
, Yu, D.
Monash University, Department of Biochemistry and Molecular
Biology, Melbourne, Australia,
Walter and Eliza Hall Institute
of Medical Research, Melbourne, Australia,
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
Mapping regulatory networks in human regulatory T cells
by chromatin conformation capture
, Bandara, V.
, Brown, C.
, Beyer, M.
, Schultze, J.
, Forrest, A.
, Barry, S.
Molecular Immunology, Robinson Research Institute,
Women’s and Children’s Health Network,
Gastroenterology, Adelaide, Australia,
LIMES, University of Bonn,
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
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.
A combinatorial threshold model for effector differentiation
T cells mediated by Blimp-1 and T-bet
, Xin, A.
, Liao, Y.
, Preston, S.
, Guan, T.
, Olshansky, M.
, Lin, J.-X.
, Li, P.
, Speed, T.P.
, Smyth, G.K.
, Leonard, W.J.
, Pellegrini, M.
, Kaech, S.
, Nutt, S.L.
, Belz, G.T.
, Kallies, A.
Olivia Newton-Jonh Cancer Research Institute, Cancer
Inflammation Laboratory, Heidelberg, Australia,
Walter & Eliza
Hall Institute, Parkville, Australia,
University of Melbourne,
Department of Medical Biology, Parkville, Australia,
School of Medicine, Department of Immunobiology, New Haven,
University of Melbourne, Department of Computing
and Information Systems, Parkville, Australia,
Lung and Blood Insitute, NIH, Bethesda, United States,
of Melbourne, Department of Mathematics and Statistics, Parkville,
La Trobe University, School of Cancer Medicine,
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
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
. 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,