2. Follicular Helper T Cells 2
Introduction
The characterization and activity of follicular helper T cells represents a relevant and
modern research area in immunology. Follicular helper T cells were first discovered in
secondary lymphoid tissue with the signature characteristic of expressing CXC chemokine
receptor 5 (CXCR5) (Breitfeld et al., 2000). CXCR5 helps follicular helper T cells migrate
towards B cell follicles in secondary lymphoid tissue and is not expressed by other types of
helper T cells in notably high levels. Follicular helper T cells rely on interleukin-21 (IL-21) and
play an important role in the development of the humoral immune response (Nurieva et al.,
2008). Furthermore, while all helper T cells express CD4 and are thus CD4+, follicular helper T
cells constitute a distinct CD4+ helper T cell lineage in that their generation is dependent on IL-
21, IL-6, and signal transducer and activator of transcription 3 (STAT3), but independent of
transforming-growth factor β (TGF-β) unlike T helper 17 cells. The main function of follicular
helper T cells is to provide signals for B cell survival and proliferation in B cell follicles of
secondary lymphoid tissue, which helps B cells undergo somatic hypermutation and isotype
switching to yield high affinity antibody-producing plasma cells and memory cells (Chen et al.,
2012). Immune system pathologies involving follicular helper T cells are related to the
overproduction of high affinity antibodies and to the generation of self-reactive antibodies
(Shekhar and Yang, 2012). Follicular helper T cells are involved in immune system pathologies
that include autoimmunity, immunodeficiency, lymphoma, and IgE-mediated allergic disease
(Yang, 2012).
Lineage and Development
During activation of a CD4+ naïve T cell in secondary lymphoid tissue, the CD4+ naïve
T cell’s T cell receptor binds to an antigen being presented on a class II major histocompatibility
3. Follicular Helper T Cells 3
complex molecule (MHC-II) on a professional antigen-presenting cell. The professional antigen-
presenting cell provides three key signals that activate and allow the CD4+ naïve T cell to
differentiate into a specific helper T cell subset: the MHC-II-peptide antigen complex binding to
the T cell receptor and CD4 co-receptor, the co-stimulatory signal from CD28 binding to its
ligand B7 on the antigen-presenting cell, and the cytokine profile conferred by the bound
antigen-presenting cell. CD4+ naïve T cells are signaled to differentiate into follicular helper T
cells under a cytokine environment that includes IL-6 and IL-21 (Nurieva et al., 2009). IL-6 and
IL-21, without the presence of TGF-β, increase the expression of the transcriptional factor B cell
lymphoma 6 (Bcl6), which is responsible for inducing the expression of genes related to
follicular helper T cells and inhibiting the expression of genes related to other helper T cell
subsets. Bcl6 is the major transcription factor associated with follicular helper T cells and is also
important for the effector function of follicular helper T cells (Johnston et al., 2009).
Follicular helper T cell generation requires a more specific co-stimulatory signal that
includes the binding of inducible co-stimulator (ICOS) to ICOS ligand (ICOSL) on B cells
(Nurieva et al., 2008). ICOS is a member of the CD28 family and is expressed by CXCR5+
CD4+ T cells, whereas B cells constitutively express ICOSL. The binding of ICOS to ICOSL is
required for the production if IL-21 by the CXCR5+ CD4+ T cell and its subsequent
differentiation into a follicular helper T cell.
Production of IL-21 by undifferentiated follicular helper T cells is induced by the binding
of ICOS to ICOSL on B cells and by the binding of IL-6 to its given receptor on the helper T cell
(Nurieva et al., 2008). IL-6 and IL-21 both exert their effects through the transcriptional factor
STAT3; IL-6, IL-21, and STAT3 are all required for differentiation of follicular helper T cells.
IL-21 acts in an autocrine fashion by binding to IL-21 receptors on the undifferentiated follicular
4. Follicular Helper T Cells 4
helper T cell’s surface to aid in development. However, the presence of IL-21 with TGF-β will
guide the helper T cell towards the helper T 17 cell lineage. Furthermore, IL-21 is the cytokine
through which follicular helper T cells assist B cells in somatic hypermutation and isotype
switching in follicles within secondary lymphoid tissue.
Transcription factors Bcl6 and Blimp-1 are antagonistic from the perspective of follicular
helper T cells in that Blimp-1 down-regulates the expression of Bcl6, which effectively blocks
the differentiation of follicular helper T cells (Johnston et al., 2009). Bcl6 and Blimp-1 are also
antagonistic regulators of the differentiation of B cells within germinal centers of secondary
lymphoid tissue, which is where follicular helper T cells exert their effector function. Bcl6 and
Blimp-1 transcriptional factors reciprocally control both the development of follicular helper T
cells and the development of B cells within B-cell regions of secondary lymphoid tissues. Future
uses of Blimp-1 may include blocking the differentiation of follicular helper T cells to prevent
the formation of antibodies that recognize self-peptides.
Follicular helper T cell differentiation has two stages: the priming stage and the
maintenance stage (Chen et al., 2012). The priming stage is dependent on the binding of an
antigen-presenting cell, which sends important signals to the developing helper T cell. ICOS
binds to ICOSL on the dendritic cell, inducing the expression of Bcl6 transcriptional factor,
which up-regulates CXCR5 expression and enables their migration towards B cell follicles in
secondary lymphoid tissue. The maintenance stage is dependent on signaling between the T-B
cell conjugate and includes an early integrin-dependent phase and a late signaling lymphocyte
molecule-associated protein (SAP) – dependent phase. B cells are required for later maintenance
of follicular helper T cells. Interactions between B cells and follicular helper T cells while they
are bound together as a conjugate are mutually beneficial for both cells (Yang, 2012).
5. Follicular Helper T Cells 5
Immunological Function
The expression of CXCR5 by follicular helper T cells aids in their migration towards B
cell follicles in secondary lymphoid tissue (Breitfeld et al., 2000). Follicular helper T cells
follow a gradient of CXCR5’s ligand, B lymphocyte chemoattractant (BLC), also known as
CXCL13, released from B cell follicles. Within B cell follicles follicular helper T cells express
CD40 ligand (CD40L), which is required for B cell development and formation of the T-B cell
conjugate, and ICOS, which is engaged by ICOSL on B cells for production of IL-21 by the
follicular helper T cell. Furthermore, IL-21 is required for follicular helper T cell generation and
the formation of germinal centers (Spolski and Leonard, 2009). IL-21 is a type I cytokine that
acts through IL-21R, a type I cytokine receptor of the IL-2 receptor subfamily. IL-21 is also
important for B cell proliferation and differentiation, including somatic hypermutation and
isotype switching, and may be referred to as the B cell stimulating cytokine (Chen et al., 2012).
Since follicular helper T cells produce IL-21, they have an important role in the development of
humoral immunity.
The main characteristics of follicular helper T cells includes the expression of CXCR5,
ICOS, SAP, and Bcl6 transcriptional factor, the production of IL-21, and the homing towards B
cell follicles in secondary lymphoid tissue. (Chen et al., 2012). Follicular helper T cells secrete
IL-10, along with IL-6 and IL-21, which also assists in somatic hypermutation and isotype
switching during B cell activation. The expression of SAP by follicular helper T cells is required
for germinal center formation and T-B cell conjugate interactions within germinal centers;
however, SAP has no impact on the interactions between T cells and dendritic cells within
follicles. A detailed description of the main function of follicular helper T cells is that they
enhance the formation of high-affinity B cells and plasma cells at germinal centers of secondary
6. Follicular Helper T Cells 6
lymphoid tissue. Once naïve B cells are signaled by antigen-presenting cells to form germinal
centers in B cell regions and isotype switching of secondary lymphoid tissues, follicular helper T
cells signal B cells through the expression of CD40 ligand binding to CD40 to suppress the
transcriptional factor Bcl6 within the B cells via an NFκB pathway. The suppression of Bcl6
removes the inhibition of gene expression involved in activation and differentiation of B cells
into plasma cells. Follicular helper T cells in germinal centers also provide other key signals for
B cell survival, which compete with Fas/FasL interactions that would induce apoptosis. Such
signals provided by the follicular helper T cell include CD40L, PD-1, BAFF, IL-4, and IL-21.
Ultimately the B cell undergoes somatic hypermutation and isotype switching and eventually
differentiates into plasma cells. Since different cytokine environments dictate the isotype formed
during isotype switching, follicular helper T cells may exhibit plasticity regarding the cytokines
they have the ability to synthesize, or different subsets of follicular helper T cells may exist
(Yang, 2012).
Involvement in Immune Pathologies
Follicular helper T cells are involved in systemic autoimmunity, which includes lupus,
via the production of high affinity auto-antibodies (Linterman et al., 2009). High affinity auto-
antibodies may form from the failure of negative selection during the B cell development or from
enhanced positive selection by follicular helper T cells. Uncontrolled generation of follicular
helper T cells can cause an increase in antibody production related to systemic autoimmunity
(Awasthi and Kuchroo, 2009). The transcriptional factor Blimp-1 may help maintain tolerance
by inhibiting Bcl6, providing a biological reason for their antagonism and an explanation for the
pathogenesis of systemic autoimmunity. Systemic lupus erythematosus patients have auto-
reactive B cells within germinal centers that eventually form auto-antibodies (Shekhar and Yang,
7. Follicular Helper T Cells 7
2012). Follicular helper T cells are clearly involved in systemic autoimmunity, which makes
sense in terms of their immunological function.
Follicular helper T cells are involved in immunodeficiency and lymphoma (Shekhar and
Yang, 2012). Follicular helper T cell involvement in immunodeficiency presents medically as an
absence of memory B cells, germinal centers, and antibodies, and may involve mutations of
ICOS, CD40L, and SAP on follicular helper T cells and other types of T cells. Due to their
importance in B cell development, follicular helper T cells may have a role in B cell lymphoma
as well.
Follicular helper T cells may be involved in IgE-mediated allergic disease. They produce
CD40L and IL-4, which contribute to the IgE response (Yang, 2012). Furthermore, IL-21 from
follicular helper T cells is linked to IgE by virtue of its involvement in isotype switching in B
cells. The understanding of the relationships between various pathologies and cellular roles in
the immune system is becoming more intricate, such that the roles of certain cells and
compounds in various pathologies are being revealed.
Conclusion
Follicular helper T cells are a unique subset of CD4+ T cells that express CXCR5 to
migrate towards B cell follicles in secondary lymphoid tissue and produce various compounds,
including IL-21, that are involved in aiding B cells in somatic hypermutation and isotype
switching to produce plasma cells that generate high affinity antibodies. The transcriptional
factor Bcl6 regulates the expression of follicular helper T cell genes and is antagonistic with the
transcriptional factor Blimp-1. Follicular helper T cells are involved in various immunological
pathologies, including autoimmunity, immunodeficiency, and IgE-mediated allergic disease, and
modern research involving follicular helper T cells is currently in progress.
8. Follicular Helper T Cells 8
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