Th1 and Th2 cell differentiation
Naive CD4+ T cells are activated by recognition of a peptide antigen-class II major
histocompatibility complex (MHC class II) presented on
antigen-presenting cells (APCs) through interaction with the T-cell receptor
(TCR alpha/beta). After activation, CD4+ T cells begin to
divide and/or give rise to a clone of effector cells, each specific for the same
antigen-class II MHC complex. These effector CD4+ T cells can be divided into three main
types, T helper type-1 (Th1), Th type-2 (Th2), and Th type-17 (Th17), with distinct
cytokine-secretion phenotypes. Th1 cells secrete mainly Interferon gamma
(IFN-gamma), which allows these cells to be particularly
effective in protecting against viruses and bacteria.
IFN-gamma activates macrophages, enhancing their ability to
phagocytoseand destroy microbes. Th2 cells produce mainly Interleukin 4
(IL-4), IL-5, and
IL-13, which up-regulate antibody production and target
parasitic organisms. IL-4 and
IL-13 induce B cell switching to IgE production, whereas
IL-5 is the principal eosinophil-activating cytokine,
mediating allergic reaction. In broad terms, Th1 cells mediate a cellular immune response
and Th2 cells potentiate a humoral immune response .
Until recently Th1 and Th2 cell subsets were considered to be the only types of CD4+
effector responses. Studies over the last few years have discovered a new subset known as
Th17 cells. These cells preferentially produce IL-17, IL-17F, and IL-22 as their
signature cytokines and play an integral role in tissue inflammation and activation of
Direct contact of APCs with T cells is the first step in Th cell differentiation.
Pathogen-associated molecular patterns are recognized by APCs (macrophages and dendritic
cells), which present antigenic components (Antigen) bound
to MHC class II. APCs mould the T-cell response in
accordance with the nature of the invading pathogen. Pathogens express
pathogen-associated molecular patterns that activate APCs directly through ligation of
pattern recognition receptors. The most common receptors involved in pattern recognition
are the Toll-like receptors (TLRs), which discriminate between different types of
pathogens . TLR signaling leads to the activation of Nuclear factor of
kappa-B (NF-kB), the main transcription factor involved in
cytokine production .
Stimulation of TCR alpha/beta/
CD3 complex on T cells by MHC class
II on APCs initiates a T cell signaling cascade leading to the activation
of Nuclear factors of activated T-cells, e.g. NF-AT1(NFATC2)
and NF-AT2(NFATC1), NF-kB, and
transcription factors of the Activator protein 1 (AP-1)
family , , , . These
transcription factors activate Interleukin 2 (IL-2)
production and increase T cell proliferation .
In addition to TCR alpha/beta, a whole set of
cell-surface receptors are also engaged by their ligands on APCs, which regulate the Th
differentiation program. CD4 acts as a cellular adhesion
molecule that binds MHC class II and stabilizes the
interaction of T cells and APCs , .
CD28 is the most notable costimulatory receptor on T cells.
It binds CD80 and CD86 on
activated APCs . The TCR alpha/beta /
CD3 complex provides a first signal for T cell activation,
and CD28 provides the second. Both signals are required for
Interleukin 2 (IL-2) production and T cell proliferation.
CD40 ligand (CD40L), which is expressed by activated T
cells, binds to CD40 on APCs. This interaction is crucial
for T-cell-mediated immune response .
IL-12 is considered to be the main cytokine driving Th1
cell differentiation. IL-12 is produced mainly by
macrophages and dendritic cells, but also by monocytes, neutrophils, and B cells in
response to different pathogens. IL-12 induces
IFN-gamma production in natural killer (NK) cells, APCs and T cells, an
effect that is synergistically enhanced by the unrelated cytokine
IL-18. IFN-gamma is also
produced by APCs as a result of the TLR signaling pathway in response to bacteria and
viruses , .
IL-12 binds to the IL-12
receptor, which is composed of two subunits, IL-12R beta 1 and IL-12R beta
2 (IL-12RB2). IL-12 receptor
activates the Janus kinases (Tyk2 and
JAK2) and the Transcription factor signal transducer and
activator of transcription 4 (STAT4), which up-regulates
IFN-gamma and IL-12RB2
gene expression .
IFN-gamma attachment to IFN-gamma
receptor leads to the JAK1- and
JAK2-mediated activation of the transcription factor
STAT1 that then induces expression of the another
transcription factor, T-box 21 (T-bet).
T-bet increases expression
of IFN-gamma and
IL-12RB2, which reinforces
IL-12 and IFN-gamma signaling pathways , , .
IL-4 is the main cytokine driving Th2 cell
differentiation. IL-4 can be produced by many cell types,
such as mast cells, basophils, eosinophils, NK cells, activated CD4+ T cells and
differentiated Th2 cells . IL-4 binds to
IL-4 receptor, type I (IL-4R type I), which induces
JAK1 / STAT6 signaling in T
cells. STAT6, in turn, activates the expression of
transcription factors GATA binding protein 3 (GATA-3) and
v-Maf musculoaponeurotic fibrosarcoma oncogene homolog
(c-Maf), leading to IL-4,
IL-5, and IL-13
production , , .
Differentiated Th cells suppress the development of their opposing cell subset. For
instance, they inhibit expression of the opposing cytokine genes . In Th1
cells, the Runt-related transcription factor 3 (RUNX3) is
induced in a T-bet-dependent manner, and both transcription
factors T-bet and RUNX3
regulate maximal production of IFN-gamma and silencing of
the gene encoding IL-4, the main cytokine required for Th2
cell differentiation . GATA-3, the key
transcription factor of Th2 cell differentiation, significantly inhibits expression of
IFN-gamma, the main cytokine produced by Th1 cells , .
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