IL-21 and T follicular helper cells
Rosanne Spolski
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Warren J. Leonard
0
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Laboratory of Molecular Immunology, National Heart
, Lung,
and Blood Institute
, Building 10, Room 7B05,
Bethesda, MD 20892-1674, USA
Upon encounter with antigen, CD41 T cells differentiate into effector Th subsets with distinctive functions that are related to their unique cytokine profiles and anatomical locations. One of the most important Th functions is to provide signals to developing B cells that induce specific and appropriate antibody responses. The major CD41 T cell subset that helps B cells is the T follicular helper (TFH) cell, whose expression of the chemokine receptor CXCR5 [chemokine (C-X-C motif) receptor 5] serves to localize this cell to developing germinal centers (GCs) where it provides instructive signals leading to Ig class switching and somatic mutation. TFH cells produce high levels of IL-21, a cytokine that is critical for GC formation and also for the generation of TFH cells. Although TFH cells have been found to produce cytokines characteristic of other Th subsets, they represent a distinct lineage whose development is driven by the transcription factor B-cell CLL lymphoma-6 (BCL6). Consistent with their critical role in the generation of antibody responses, dysregulated TFH function has been associated with the development of systemic autoimmunity. Here, we review the role of IL-21 in the regulation of normal TFH development and function as well as in progression of autoimmune responses.
Introduction
Specific CD4+ T cell effector responses can be delegated
to distinct subsets characterized as Th1, Th2, Th17 or
regulatory T cell (Treg) cells, with the development of each of
these subsets being driven, respectively, by the master
lineage-specific transcription factors T-bet [now also denoted
as T-box 21 (TBX21)], GATA binding protein 3 (GATA-3),
retinoid-related orphan receptor ct (RORct) or forkhead box
protein P3 (FOXP3) (1). T-cell-dependent antibody production
is a critical component of the normal immune response, and
Th2 cells were originally believed to be the predominant
source of B cell help because of their production of IL-4, a
cytokine known to be involved in B cell proliferation as well
as Ig class switching (1).
Subsequently, IL-21 was identified as a Th-derived, type I,
four-a-helical bundle cytokine that was critical for plasma cell
generation as well as isotype switching (2) and normal Ig
production (3), consistent with IL-21 being a Th2-specific
cytokine (4); however, other data indicated that IL-21 had
Th1like properties as well (5).
More recently it became clear that the CD4+ T cells involved
in germinal center (GC) formation and functiondenoted
T follicular helper cells (TFH cells)were distinct from any
of these previously identified subsets. These TFH cells
expressed high levels of the chemokine receptor CXCR5
[chemokine (CXC motif) receptor 5], allowing them to home
to and be retained by the lymphoid follicle, where contact with
antigen-primed B cells led to B cell proliferation, isotype
switching and somatic mutation of the Ig repertoire (6, 7).
Gene microarray analysis revealed that follicle-localized
CXCR5+ Th cells had a very distinctive transcriptional profile
that distinguished these cells from Th1 or Th2 cells, with
highlevel IL-21 and B-cell CLL lymphoma-6 (BCL6) messenger
RNAs (mRNAs) (5), both of which are now considered
hallmarks of TFH cells (6).
IL-21 is a type I cytokine that signals via a specific
receptor protein, IL-21R (8, 9), and the common cytokine
receptor c chain, cc, which is shared by the receptors for
IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21 (10); cc is mutated in
humans with X-linked SCID (11). IL-21 signals in part via
STAT3 (signal transducer and activator of transcription 3)
(12), with actions on a wide range of lineages, including
T cells, B cells, NK cells and dendritic cells (10). Specifically,
IL-21 can promote the expansion of CD8+ T cells, is critical
for normal Ig production by B cells, can inhibit dendritic cell
function and, interestingly, can be pro-apoptotic for B cells
and NK cells (10). Whereas IL-21 was first identified as
a cytokine produced by activated peripheral blood T cells (9),
it is now known that it can be produced by a range of
differentiated Th populations (10) as well as by NKT cells (13).
In this review, we discuss the role of IL-21 in the
generation of TFH cells as well as in the functional interaction of
these cells with B cells within the GC. The relationship
between TFH and other Th subsets will also be discussed, as
more evidence mounts in support of flexibility of cytokine
profiles within the TFH cells. In addition, the role played by
IL-21 in the interaction between the TFH master transcription
factor BCL6 and other lineage-specific transcription factors
will be discussed. Finally, elevated levels of IL-21 and
TFHspecific surface molecules have been implicated in the
development of systemic autoimmune responses, and the
mechanisms for disease developmen (...truncated)