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Helper Cell Genetic Program
Transcription Factors in the T Follicular
Bcl6: Divergent Roles of STAT Family
Type I IFN Induces Binding of STAT1 to
Golnaz Vahedi, Hong-wei Sun, Yuka Kanno and John J.
Hirahara, Jennifer L. Cannons, Pamela L. Schwartzberg,
Hayato Takahashi, Masanari Kato, Shigeru Iwata, Kiyoshi
Shingo Nakayamada, Amanda C. Poholek, Kristina T. Lu,
2014; 192:2156-2166; Prepublished online 31
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The Journal of Immunology
Type I IFN Induces Binding of STAT1 to Bcl6: Divergent
Roles of STAT Family Transcription Factors in the
T Follicular Helper Cell Genetic Program
Shingo Nakayamada,*,1,2Amanda C. Poholek,*,1Kristina T. Lu,†Hayato Takahashi,*,3
Masanari Kato,* Shigeru Iwata,* Kiyoshi Hirahara,*,4Jennifer L. Cannons,†
Pamela L. Schwartzberg,†Golnaz Vahedi,* Hong-wei Sun,‡Yuka Kanno,* and
John J. O’Shea*
CD4+T follicular helper cells (TFH) are critical for the formation and function of B cell responses to infection or immunization,
but also play an important role in autoimmunity. The factors that contribute to the differentiation of this helper cell subset are
incompletely understood, although several cytokines including IL-6, IL-21, and IL-12 can promote TFHcell formation. Yet, none
of these factors, nor their downstream cognate STATs, have emerged as nonredundant, essential drivers of TFHcells. This suggests
a model in which multiple factors can contribute to the phenotypic characteristics of TFHcells. Because type I IFNs are often
generated in immune responses, we set out to investigate whether these factors are relevant to TFHcell differentiation. Type I IFNs
promote Th1 responses, thus one possibility was these factors antagonized TFH-expressed genes. However, we show that type I
IFNs (IFN-a/b) induced B cell lymphoma 6 (Bcl6) expression, the master regulator transcription factor for TFHcells, and CXCR5
and programmed cell death-1 (encoded by Pdcd1), key surface molecules expressed by TFHcells. In contrast, type I IFNs failed to
induce IL-21, the signature cytokine for TFHcells. The induction of Bcl6 was regulated directly by STAT1, which bound to the
Bcl6, Cxcr5, and Pdcd1 loci. These data suggest that type I IFNs (IFN-a/b) and STAT1 can contribute to some features of TFHcells
but are inadequate in inducing complete programming of this subset.
immune response. One of the oldest described functions of CD4+
T cells is to mediate help to B cells and influence the Ab response
to infection or immunization (1–3). More recently this activity has
been attributed to a defined subset of cells termed T follicular
The Journal of Immunology, 2014, 192: 2156–2166.
n response to microbial pathogens, CD4+T cells have the
capacity to differentiate into multiple, distinct effector sub-
sets, each with a specific and unique role in the adaptive
helper (TFH) cells, whose primary task is to drive the formation of
B cell responses and provide helper function (4). TFHcells are
commonly identified by high surface expression of the chemokine
receptor, CXCR5, and the inhibitory receptor programmed cell
death-1 (PD-1) (5–8). CXCR5 expression allows TFHcells to mi-
grate from the T cell zone to the B cell follicle where they local-
ize to the germinal center (GC), and mediate B cell help via cell-
cell contact using the costimulatory molecules CD40-Ligand and
ICOS (5, 9), and secretion of the cytokines IL-21 and IL-4 (10–
16). In addition, the signaling lymphocytic activation molecule–
associated protein (SAP) is critical for T cell–B cell interaction
(17–19). GCs are the site of high-affinity Ag specific Ab pro-
duction, memory B cell formation, and long-lived plasma cell
differentiation. Deficiencies in TFHcell function in the absence of
ICOS or SAP, or the absence of CD40-Ligand, or double defi-
ciency in IL-21 and IL-4, all result in severely diminished or ab-
sent B cell responses including reduced total Ag specific Ab and
skewed isotype responses (20–27).
The master regulator transcription factor required for TFHcell
formation is the transcriptional repressor B cell lymphoma 6 (Bcl6)
(28–30). In the absence of Bcl6, TFHcells are unable to form, and
subsequently GCs are not present (28). Like other master regulators,
overexpression of Bcl6 not only enforces TFHcell differentiation but
also attenuates differentiation to other fates by repressing the ex-
pression of master transcription factors for other CD4+T cell sub-
sets, including T-bet, GATA3, and Rorg-t (29, 31).
CD4+T cell subset differentiation is mediated in large part by
exposure to various cytokines. For example, Th1 cells develop in
the presence of IL-12 and IFN-g, whereas Th2 cells form after
exposure to IL-4 (1). For TFHcells, several cytokines have been
reported to effect differentiation. In vitro, exposure of CD4+T cells
to the cytokines IL-6 and IL-21 drives a TFH-like phenotype (30,
*Lymphocyte Biology Section, Molecular Immunology and Inflammation Branch,
National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Insti-
tutes of Health, Bethesda, MD 20892;†National Human Genome Research Institute,
National Institutes of Health, Bethesda, MD 20892; and‡Biodata Mining and Dis-
covery Section, National Institute of Arthritis and Musculoskeletal and Skin Dis-
eases, National Institutes of Health, Bethesda, MD 20892
1S.N. and A.C.P. contributed equally to this work.
2Current address: First Department of Internal Medicine, University of Occupational
and Environmental Health, Kitakyushu, Japan.
3Current address: Department of Dermatology, Keio University School of Medicine,
4Current address: Department of Advanced Allergology of the Airway, Graduate
School of Medicine, Chiba University, Chiba, Japan.
Received for publication March 13, 2013. Accepted for publication January 3, 2014.
This work was supported by the Intramural Research Programs of the National In-
stitute of Arthritis and Musculoskeletal and Skin Diseases and the National Human
Genome Research Institute, the Postdoctoral Research Associate Program, the Na-
tional Institute of General Medical Sciences, the National Institutes of Health (to
A.C.P. and K.T.L.), and the Japan Society for the Promotion of Science Research
Fellowship for Japanese Biomedical and Behavioral Researchers at the National
Institutes of Health (to K.H.).
Address correspondence and reprint requests to Dr. Amanda C. Poholek, National
Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of
Health, 10 Center Drive, Room 13C120, Bethesda, MD 20892. E-mail address:
Abbreviations used in this article: Bcl6, B cell lymphoma 6; ChIP, chromatin immu-
noprecipitation; GC, germinal center; PD-1, programmed cell death-1; qPCR, quan-
titative PCR; seq, sequencing; TFH, T follicular helper.
by guest on December 21, 2015
J. Lay (Flow Cytometry Section, National Institute of Arthritis and Muscu-
loskeletal and Skin Diseases) for their technical support.
The authors have no financial conflicts of interest.
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