I-Cheng Ho

IL-4 inhibits TGF-beta-induced Foxp3+ T cells and, together with TGF-beta, generates IL-9+ IL-10+ Foxp3(-) effector T cells.

Transcription factor Foxp3 is critical for generating regulatory T cells (Treg cells). Transforming growth factor-β (TGF-β) induces Foxp3 and suppressive Treg cells from naive T cells, whereas interleukin 6 (IL-6) inhibits the generation of inducible Treg cells. Here we show that IL-4 blocked the generation of TGF-β-induced Foxp3+ Treg cells and instead induced a population of T helper cells that produced IL-9 and IL-10. The IL-9+IL-10+ T cells demonstrated no regulatory properties despite producing abundant IL-10. Adoptive transfer of IL-9+IL-10+ T cells into recombination-activating gene 1–deficient mice induced colitis and peripheral neuritis, the severity of which was aggravated if the IL-9+IL-10+ T cells were transferred with CD45RBhi CD4+ effector T cells. Thus IL-9+IL-10+ T cells lack suppressive function and constitute a distinct population of helper-effector T cells that promote tissue inflammation.

The Proto-Oncogene c-maf Is Responsible for Tissue-Specific Expression of Interleukin-4

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.

The costimulatory molecule ICOS regulates the expression of c-Maf and IL-21 in the development of follicular T helper cells and TH-17 cells.

The inducible costimulatory molecule ICOS has been suggested to be important in the development of interleukin 17 (IL-17)-producing helper T cells (TH-17 cells) and of follicular helper T cells (TFH cells). Here we show that ICOS-deficient mice had no defect in TH-17 differentiation but had fewer TH-17 cells after IL-23 stimulation and fewer TFH cells. We also show that TFH cells produced IL-17 and that TFH cells in ICOS-deficient mice were defective in IL-17 production. Both TH-17 and TFH cells had higher expression of the transcription factor c-Maf. Genetic loss of c-Maf resulted in a defect in IL-21 production and fewer TH-17 and TFH cells. Thus our data suggest that ICOS-induced c-Maf regulates IL-21 production that in turn regulates the expansion of TH-17 and TFH cells.

The Transcription Factor c-Maf Controls the Production of Interleukin-4 but Not Other Th2 Cytokines

IL-4 promotes the differentiation of naive CD4+ T cells into IL-4-producing T helper 2 (Th2) cells. Previous work provided suggestive but not conclusive evidence that the transcription factor c-Maf directed the tissue-specific expression of IL-4. It was not known whether c-Maf controlled the transcription of other Th2 cytokine genes. To elucidate the role of c-Maf in vivo, we examined cytokine production in mice lacking c-Maf (c-maf(-/-)). CD4+ T cells and NK T cells from c-maf(-/-) mice were markedly deficient in IL-4 production. However, the mice produced normal levels of IL-13 and IgE, and, when differentiated in the presence of exogenous IL-4, c-maf(-/-) T cells produced approximately normal levels of other Th2 cytokines. We conclude that c-Maf has a critical and selective function in IL-4 gene transcription in vivo.

Cutting edge: IL-27 induces the transcription factor c-Maf, cytokine IL-21, and the costimulatory receptor ICOS that coordinately act together to promote differentiation of IL-10-producing Tr1 cells.

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.

GATA-3 deficiency abrogates the development and maintenance of T helper type 2 cells

T helper type 2 (Th2) cells secrete IL-4, IL-5, IL-10, and IL-13 and mediate allergic and asthmatic disease. GATA-3 is a Th2-specific transcription factor that appears in overexpression studies and transgenic systems to function as a Th2 lineage determinant. Because GATA-3 is also crucial for development of the T lineage and throughout thymic development, direct demonstration that GATA-3 is required for Th2 development by targeted deletion has been lacking. Using a conditional knockout approach, we found that GATA-3 is required for optimal Th2 cytokine production in vitro and in vivo. Our data also show that GATA-3 expression must be sustained to maintain the Th2 phenotype.

Human GATA-3: a lineage-restricted transcription factor that regulates the expression of the T cell receptor alpha gene.

In addition to its role in the recognition of foreign antigens, the T cell receptor (TCR) alpha gene serves as a model system for studies of developmentally‐regulated, lineage‐specific gene expression in T cells. TCR alpha gene expression is restricted to cells of the TCR alpha/beta+ lineage, and is controlled by a T cell‐specific transcriptional enhancer located 4.5 kb 3′ to the C alpha gene segment. The TCR alpha enhancer contains four nuclear protein binding sites called T alpha 1‐T alpha 4. In this report we describe the identification and characterization of a novel human cDNA, hGATA‐3 that binds to the T alpha 3 element of the human TCR alpha enhancer. hGATA‐3 contains a zinc finger domain that is highly related to the DNA‐binding domain of the erythroid‐specific transcription factor, GATA‐1, and binds to a region of T alpha 3 that contains a consensus GATA binding site (AGATAG). Northern blot analyses of hematopoietic cell lines demonstrate that hGATA‐3 is expressed exclusively in T cells. Overexpression of hGATA‐3 in HeLa cells or human B cells specifically activated transcription from a co‐transfected reporter plasmid containing two copies of the T alpha 3 binding site located upstream of the minimal SV40 promoter. Taken together these results demonstrate that hGATA‐3 is a novel lineage‐specific hematopoietic transcription factor that appears to play an important role in regulating the T cell‐specific expression of the TCR alpha gene.

The Transcription Factor NFAT4 Is Involved in the Generation and Survival of T Cells

Nuclear factor of activated T cells (NFAT) is a family of four related transcription factors implicated in cytokine and early response gene expression in activated lymphocytes. Here we report that NFAT4, in contrast to NFATp and NFATc, is preferentially expressed in DP thymocytes. Mice lacking NFAT4 have impaired development of CD4 and CD8 SP thymocytes and peripheral T cells as well as hyperactivation of peripheral T cells. The thymic defect is characterized by increased apoptosis of DP thymocytes. The increased apoptosis and hyperactivation may reflect heightened sensitivity to TcR-mediated signaling. Further, mice lacking NFAT4 have impaired production of Bcl-2 mRNA and protein. NFAT4 thus plays an important role in the successful generation and survival of T cells.

Critical Roles for Transcription Factor GATA-3 in Thymocyte Development

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.

Transcription: Tantalizing Times for T Cells

The T helper lymphocyte is responsible for orchestrating an appropriate immune response to pathogens. To do so, it has evolved into two specialized subsets that direct type 1 and type 2 immunity. Here, we discuss the genetic programs that control lineage commitment of progenitor T helper cells along each of these pathways.