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230 Part III Immunologic Basis of Hematology

Several cytokines are implicated in Th1 differentiation, but the two IL-4 produced by mature Th2 cells acts in a positive feedback loop
most critical are interferon γ (IFN-γ) and IL-12. IFN-γ produced to promote further Th2 cell differentiation in naive T cells as they
by innate immune cells promotes Th1 differentiation by activat- encounter antigen. Th2-derived IL-4 also mediates IgE class switch-
ing signal transducer and activator of transcription 1 (STAT1), a ing in B cells. Soluble IgE binds to and crosslinks its high-affinity
key signaling molecule that regulates T-bet, one of the signature receptor FcεRI on basophils and mast cells, promoting production
transcription factors associated with Th1 cells. IL-12, produced of histamine and serotonin as well as several cytokines, including
by activated APCs and other innate immune cells, acts through a IL-4, IL-13, and TNF-α. IL-5 produced from Th2 cells recruits
separate STAT4-dependent pathway to promote IFN-γ production. eosinophils, whereas Th2-derived IL-13 promotes both the expulsion
IL-12 also signals to upregulate its own receptor and the IL-18 of helminths during parasitic infection and also the induction of
receptor, thereby allowing IL-18 to act in concert with IL-12 to airway hypersensitivity.
promote IFN-γ production, thus creating a “feedforward” cycle to Th2 responses are critical for immunity against extracellular para-
amplify the Th1 response. sites, but excessive Th2 responses are associated with the pathologic
T-bet, a T-box family member, is the key transcription factor conditions of allergy and airway hypersensitivity. The increase in
associated with Th1 differentiation and function. T-bet-deficient asthma in the developed world has been linked to an imbalance
T cells are defective in their ability to differentiate into Th1 cells of Th subsets with skewing toward “Th2-ness” in the population.
either in vitro or in vivo, and T-bet-deficient mice are unable to Additional work is necessary to more firmly establish a molecular
control Leishmania major infection, a well-characterized intracellular immunologic link to the epidemiology of these diseases.
pathogen model that depends on the characteristic Th1 cytokines for
pathogen clearance. Whereas T-bet is considered the “essential” factor
that directs Th1 lineage determination, other transcription factors, Th17 Cells
such as Runx3 and Hlx, are important for optimal Th1 function.
Once differentiated, Th1 effector cells are characterized by pro- The original description of Th1 and Th2 cells, indicating that not
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duction of proinflammatory cytokines such as IFN-γ and tumor all mature CD4 T cells were alike, led to the search for other
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necrosis factor-α (TNF-α) that stimulate macrophages, NK cells, and CD4 subsets. Studies exploring the role of IL-23 in experimental
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CD8 T cells to promote pathogen clearance. It is clear, however, that autoimmune disease models found IL-23 to be critical for the gen-
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Th1 function must be balanced. Evidence from both animal models eration of an IL-17-producing CD4 T-cell population, designated
and human patients indicates that overexuberant Th1 responses drive Th17 cells. Extensive analyses of IL-17 and the cells that produce
inflammatory conditions and may lead to tissue destruction. this cytokine demonstrate that Th17 cells are important for the
control of extracellular bacterial and fungal infections. With excessive
activity, however, these cells also appear to play an important role in
Th2 Cells autoimmune diseases through the production of proinflammatory
cytokines, including IL-17A, IL-17F, IL-21, and IL-22.
Th2 cells are critical for the immune response against extracellular Although IL-23 is a key regulator of Th17 cells, the IL-23 receptor
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parasites, such as helminths, through production of IL-4, IL-5, and is not expressed on naive CD4 cells and hence could not explain
IL-13. At initial sites of parasitic infection, epithelial cells of the the differentiation of cells into the Th17 subset. Subsequent studies
target organs, including the skin, lungs, and intestines, and resident demonstrated that the combination of transforming growth factor-β
cells of the innate immune system sense parasite-derived products (TGF-β) with either IL-16 or IL-21 induces Th17 differentiation.
and produce Th2-inducing cytokines, including thymic stromal The cytokines that are key mediators of Th17 differentiation and
lymphopoietin (TSLP), IL-4, IL-25, and IL-33. These cytokines then survival, including IL-6, IL-21, and IL-23, all activate STAT3.
act on innate immune cells, including basophils and DCs, as well as The critical role of this STAT family member was demonstrated in
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directly on naive CD4 cells to promote Th2 differentiation. murine studies, when its deletion abrogated the ability of T cells to
Recent work has provided insight into how cytokine signaling, undergo Th17 differentiation. In humans, the importance of STAT3
particularly IL-4 signaling, promotes Th2 differentiation. Through was highlighted when it was identified as the genetic mutation
interaction with its receptor, IL-4 activates STAT6. STAT6 plays present in many patients with hyper-IgE syndrome (HIES, or Job
a vital role in Th2 differentiation, as evidenced by the profound syndrome). HIES is a rare immunodeficiency syndrome characterized
reduction in development of this lineage in Stat6-deficient mice. by recurrent staphylococcal skin abscesses, elevated serum IgE, and
STAT6 activation leads to its nuclear translocation and subsequent pneumatocele-forming pneumonias. Patients with HIES with STAT3
induction of the transcription factor GATA3, which, like T-bet for mutations have an impaired ability to form Th17 cells, which may
Th1 cells, is considered the master regulator of Th2 differentiation. explain part of their immunodeficiency. STAT3 regulates expression
GATA3 regulates Th2 cytokine production by binding and activating of many cytokine and cytokine receptor genes involved in Th17
the “Th2 locus,” which includes the genes encoding IL-4, IL-5, and generation or function, including IL-17A, IL-17F, IL-21, IL-21R,
IL-13. When GATA3 function is abrogated, Th2 differentiation is and IL-23R.
virtually absent both in vitro and in vivo. In mature differentiated STAT3 is also important for induction of the signature Th17
Th2 cells, GATA3 deficiency results in loss of IL-5 and IL-13 produc- transcription factor ROR-γt, which is a member of the retinoic acid–
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tion. GATA3 is both necessary and sufficient for Th2 differentiation related orphan receptor (ROR) family. In naive CD4 cells, ROR-γt
because forced expression either by retroviral constructs or transgenic induces IL-17 gene transcription and promotes expression of the
expression promotes Th2 differentiation and represses Th1 differ- IL-23 receptor. Overexpression of ROR-γt induces Th17 differentia-
entiation. Repression of Th1 development occurs at least partially tion, but deficiency of ROR-γt only partially affects Th17 cells in
through GATA3-dependent inhibition of STAT4, thus interfering vivo because of expression of the related transcription factor ROR-α,
with Ifng gene transcription. which is also expressed in T cells and is induced by IL-6/TGF-β in
TCR signal strength also is involved in determining if a naive a STAT3-dependent manner. Cells deficient in both ROR-γt and
T cell will differentiate into a Th1 or Th2 cell. Studies in mice ROR-α lose the ability to undergo Th17 differentiation, both in
using altered peptide ligands that have decreased affinity for par- vitro and in vivo.
ticular TCRs and experiments using limiting doses of antigen have Th17 cells are induced during the response to extracellular bacteria
demonstrated that diminished TCR stimulation promotes Th2 cell and fungi, including Klebsiella pneumoniae, Bacteroides species, and
differentiation. Differences in costimulation also affect Th2 pathway Candida albicans. Indeed, some patients with chronic mucocutaneous
differentiation. Mice deficient in CD28 or its ligand have a more candidiasis have been shown to have mutations in IL-17F and the
pronounced defect in Th2 responses, suggesting that these molecules IL-17 receptor genes. Excessive Th17 cell function also plays a role
may play a greater role in promoting Th2 differentiation than Th1 in autoimmune diseases, such as rheumatoid arthritis, psoriasis, and
differentiation. Crohn disease, and therapies targeting the IL-17/IL-23 axis have