Foxp3 is a key transcription factor involved in the generation and function of regulatory T (Treg) cells. Transforming growth factor β (TGF-β) induces Foxp3, which generates inducible Foxp3+ Treg cells from naïve T cells, and interleukin 6 (IL-6) inhibits the generation of inducible Treg cells and induces T helper cells that produce IL-17 (TH-17 cells). However, a role for IL-4 in the generation of TGF-β-induced Treg cells and/or the generation of effector CD4+ T helper cells has not been studied. Here, we show that IL-4 blocked the generation of TGF-β-induced Foxp3+ Treg cells. Instead, IL-4 induced a population of T helper cells that predominantly produce IL-9 and IL-10. The IL-9+IL-10+ T cells did not exhibit any regulatory properties in spite of producing large quantities of IL-10. Adoptive transfer of IL-9+IL-10+producing T cells into RAG-1-deficient mice induced colitis and peripheral neuritis. Interestingly, the severity of tissue inflammation was aggravated when IL-9+IL-10+ T cells were co-transferred with CD45RBhi CD4+ effector T cells into RAG-1-deficient mice, which indicated that IL-9+IL-10+ T cells do not display any suppressive function and therefore constitute a unique population of IL-10-producing helper-effector T cells that promote tissue inflammation.

The inducible costimulatory molecule (ICOS) has been suggested to play an important role in the

IL-27 has recently been identified as a differentiation factor for the generation of IL-10-producing regulatory type 1 (Tr1) T cells. However, how IL-27 induces the expansion of Tr1 cells has not been elucidated. In this study we demonstrate that IL-27 drives the expansion and differentiation of IL-10-producing murine Tr1 cells by inducing three key elements: the transcription factor c-Maf, the cytokine IL-21, and the costimulatory receptor ICOS. IL-27-driven c-Maf expression transactivates IL-21 production, which acts as an autocrine growth factor for the expansion and/or maintenance of IL-27-induced Tr1 cells. ICOS further promotes IL-27-driven Tr1 cells. Each of those elements is essential, because loss of c-Maf, IL-21-signaling, or ICOS decreases the frequency of IL-27-induced differentiation of IL-10-producing Tr1 cells.

The molecular basis for the distinctive cytokine expression of CD4+ T helper 1 (Th1) and T helper 2 (Th2) subsets remains elusive. Here, we report that the proto-oncogene c-maf, a basic region/leucine zipper transcription factor, controls tissue-specific expression of IL-4. c-Maf is expressed in Th2 but not Th1 clones and is induced during normal precursor cell differentiation along a Th2 but not Th1 lineage. c-Maf binds to a c-Maf response element (MARE) in the proximal IL-4 promoter adjacent to a site footprinted by extracts from Th2 but not Th1 clones. Ectopic expression of c-Maf transactivates the IL-4 promoter in Th1 cells, B cells, and nonlymphoid cells, a function that maps to the MARE and Th2-specific footprint. Furthermore, c-Maf acts in synergy with the nuclear factor of activated T cells (NF-ATp) to initiate endogeneous IL-4 production by B cells. Manipulation of c-Maf may alter Th subset ratios in human disease.

Interleukin 4 (IL-4) and IL-13 are critical for responses against parasitic helminthes. Here we used genetically engineered reporter mice to assess the temporal and spatial production of these cytokine in vivo. In lymph nodes, IL-4 was confined to T follicular helper (TFH) cells, however these cells did not make IL-13. In contrast, tissue type 2 helper T TH2 cells produce both cytokines. Divergent IL-4 and IL-13 production also occurred among innate immune cells, where basophils produced IL-4, while innate helper type 2 (Ih2) cells produced IL-13. IL-13 production by TH2 and Ih2 cells was dependent on high GATA-3 levels, in contrast to low GATA-3 levels in TFH cells and basophils. Distinct localization and cellular expression of IL-4 and IL-13 explains their unique roles during allergic immunity.

How breast cancers are able to disseminate and metastasize is poorly understood. Using a hyperplasia transplant system, we show that tumor dissemination and metastasis occur in discrete steps during tumor progression. Bioinformatic analysis revealed that loss of the transcription factor GATA-3 marked progression from adenoma to early carcinoma and onset of tumor dissemination. Restoration of GATA-3 in late carcinomas induced tumor differentiation and suppressed tumor dissemination. Targeted deletion of GATA-3 in early tumors led to apoptosis of differentiated cells, indicating that its loss is not sufficient for malignant conversion. Rather, malignant progression occurred with an expanding GATA-3-negative tumor cell population. These data indicate that GATA-3 regulates tumor differentiation and suppresses tumor dissemination in breast cancer.

Many advances in our understanding of the molecules that regulate the development, differentiation and function of T cells have been made over the past few years. One important regulator of T-cell differentiation is the transcription factor GATA3 (GATA-binding protein 3). Although the main function of GATA3 is to act as a master transcription factor for the differentiation of T helper 2 (T H 2) cells, new research has helped to uncover crucial functions of GATA3 in T cells that go beyond T H 2-cell differentiation, and that are important at earlier stages of haematopoietic-and lymphoid-cell development. This Review focuses on the functions of GATA3 from early thymocyte development to effector T-cell differentiation. In addition, we discuss the interactions between GATA3 and other transcription factors and signalling pathways, and highlight the functional significance of GATA3 protein structure.The GATA family of transcription factors are conserved proteins that contain one or two C2-C2-type zinc-finger motifs that recognize the consensus DNA sequence WGATAR (where W denotes A or T and R denotes A or G)1 , 2. The six members of the mammalian GATA family (GATA1 to GATA6) contain two zinc-finger motifs, which probably arose by gene duplication (FIG. 1). The different GATA proteins have distinct and restricted patterns of tissue expression and can be divided into the haematopoietic factors (GATA1, GATA2 and GATA3) and the endodermal factors (GATA4, GATA5 and GATA6). The GATA proteins have a common structure, which comprises distinct N-terminal regions that have transactivating activity, highly conserved zinc-finger motifs in the C-terminal region, conserved basic regions located immediately after the second zinc finger and distinct Cterminal regions of varying lengths (FIG. 1). GATA3 is the main GATA-family member that is expressed by immune cells, and can be easily detected in developing and mature T cells, natural killer (NK) cells and CD1-restricted NKT cells3 -5. Indeed, several recent studies have revealed an emerging role for GATA3 in invariant NKT cells (BOX 1). By contrast, mature mast cells express GATA1 and GATA2 but not GATA36 , 7. Beyond the immune system, GATA3 is expressed in many embryonic and adult tissues, including the adrenal glands, kidneys, central nervous system, inner ear, hair follicles, skin and breast tissue, and important functions in several these tissues have been demonstrated in knockout and conditional knockout mouse models8 -14 (for additional references, see REF. 15).In immune cells, GATA3 is best known to function as a master regulator of T helper 2 (T H 2)-cell differentiation. However, in recent years, GATA3 has been found to have additional crucial functions in early T-cell commitment, β-selection and CD4 + T-cell NIH Public Access

The transcription factor GATA-3 is expressed at every stage of thymic development, but its role in thymocyte differentiation is unknown. The fact that RAG chimeric animals lacking GATA-3 cannot generate early thymocytes from common lymphoid progenitors has thus far precluded investigation of the function of GATA-3 in the thymus. To address this, we generated mice deficient in GATA-3 at early and late stages of thymic differentiation. Our studies revealed that GATA-3 is involved in beta selection and is indispensable for single-positive CD4 thymocyte development. Thus, our data demonstrate that the coordinated and regulated expression of GATA-3 at each stage of thymic development is critical for the generation of mature T cells.