A novel transcription factor, T-bet, directs Th1 lineage commitment.

Much data support an essential role for interleukin (IL)-2 in immune tolerance. This idea is much different from the early paradigm in which IL-2 is central for protective immune responses. This change in thinking occurred when a T regulatory cell defect was shown to be responsible for the lethal autoimmunity associated with IL-2/IL-2R deficiency. This realization allowed investigators to explore immune responses in IL-2-nonresponsive mice rendered autoimmune-free. Such studies established that IL-2 sometimes contributes to optimal primary immune responses, but it is not mandatory. Emerging findings, however, suggest an essential role for IL-2 in immune memory. Here, the current understanding of the dual role of IL-2 in maintaining tolerance and contributing to immunity in vivo is reviewed with some emphasis on T regulatory cell production and homeostasis. Also discussed are implications of this new appreciation concerning the immunobiology of IL-2 with respect to targeting IL-2 or its receptor in immunotherapy.

The Biology of Interleukin-2

Cells of the immune system provide particularly fruitful subjects for the study of lineage commitment. Both T and B lymphocytes undergo complicated patterns of differentiation from uncommitted, nonfunctional precursor cells to highly sophisticated effector cells. The development of the helper T lymphocyte is one of the most elegant examples of this. A little over a decade ago, Mosmann and Coffman (1989) discovered that naive mouse CD4 T helper lymphocytes, upon receiving an antigenic stimulus, differentiate into two distinct subsets defined both by their function and by unique cytokine profiles. These subsets, T helper 1 (Th1) and T helper 2 (Th2) (Mosmann et al. 1986; Mosmann and Coffman 1989; Paul and Seder 1994; O’Garra 1998; Rengarajan and Glimcher 2000), are responsible for cell-mediated/inflammatory immunity and humoral responses, respectively (Fig. 1). This division of labor fits nicely with previous demonstrations that an organism tends to mount either a cell-mediated or humoral response, but not both, in response to pathogens. The function of T helper cells can largely be explained by the cytokines they secrete. Cytokines (or lymphokines) are small hormone-like polypeptides that have pleiotrophic biological activities in several cell types. Resting T cells do not transcribe cytokine genes, but they are rapidly induced upon coactivation through the T-cell receptor (TCR) and costimulatory receptors (Lenschow et al. 1996). Much progress has been made in identifying the signaling pathways and transcription factors that control Th1 and Th2 differentiation as shown schematically (Fig. 2a). This review will summarize what is currently known about the signals that regulate lineage commitment in T helper cells with a special focus on three subset-specific transcription factors, T-bet, GATA-3, and c-Maf, responsible for lineage commitment (Fig. 2b).

/pdf/lineage-commitment-in-the-immune-system-the-t-helper-aiiucfliqp.pdf

Lineage commitment in the immune system: the T helper lymphocyte grows up

Overview of interleukin-2 function, production and clinical applications.

Interleukin (IL)-10 is a pleiotropic cytokine which inhibits a broad array of immune parameters including T helper cell type 1 (Th1) cytokine production, antigen presentation, and antigen-specific T cell proliferation. To understand the consequences of altered expression of IL-10 in immune models of autoimmune disease, the response to infectious agents, and the response to tumors, we developed transgenic mice expressing IL-10 under the control of the IL-2 promoter. Upon in vitro stimulation, spleen cells from unimmunized transgenic mice secrete higher levels of IL-10 and lower amounts of IFN-gamma than do controls, although no gross abnormalities were detected in lymphocyte populations or serum Ig levels. Transfer of normally pathogenic CD4(+) CD45RBhigh splenic T cells from IL-10 transgenic mice did not cause colitis in recipient severe combined immunodeficiency mice. Furthermore, co-transfer of these transgenic cells with CD4(+) CD45RBhigh T cells from control mice prevented disease. Transgenic mice retained their resistance to Leishmania major infection, indicating that their cell-mediated immune responses were not globally suppressed. Lastly, in comparison to controls, IL-10 transgenic mice were unable to limit the growth of immunogenic tumors. Administration of blocking IL-10 mAbs restored in vivo antitumor responses in the transgenic mice. These results demonstrate that a single alteration in the T cell cytokine profile can lead to dramatic changes in immune responses in a manner that is stimulus dependent. These mice will be useful in defining differences in inflammatory conditions and cellular immunity mediated by IL-10.

/pdf/altered-immune-responses-in-interleukin-10-transgenic-mice-1ys1k2nf1e.pdf

Altered immune responses in interleukin 10 transgenic mice.

A transgenic mouse system has been established to follow the pattern of IL-2 expression at the level of single T cells. This was achieved by introducing a human IL-2 promoter-driven reporter gene (Escherichia coli lacZ) into the germline of mice and monitoring its product, beta-galactosidase (beta-gal), by FACS analysis. Ex vivo experiments confirmed that the regulated expression of the transgene is comparable with that of the endogenous IL-2 gene. Transgene expression is inducible by mitogens, restricted to T cells, and diminished by immunosuppressive agents, such as cyclosporin A, at concentrations known to suppress IL-2 transcription. Depending on the mitogens used, 30-50% of peripheral T cells produced IL-2 with an asynchronous induction pattern, as measured by transgenic beta-gal activity. Both helper (CD4+CD8-) and cytotoxic T cells (CD4-CD8+) respond with comparable heterogenous expression levels but they show different frequencies of beta-gal production. Transgenic beta-gal-producing T cells were detectable as early as 2 h after mitogen stimulation. These cells represent a transitional IL-2 secreting, IL-2 receptor alpha-chain negative T cell population, which occurs in the autocrine process of T cell activation. Administration of staphylococcal enterotoxin A (SEA), a bacterial superantigen, resulted in a T cell specific (Thy-1.2) increase (2.5-fold) of reporter gene expression in vivo. In summary, we could demonstrate that IL-2 promoter-driven reporter gene expression in transgenic mice is a sensitive tool to characterize IL-2 expressing cells phenotypically.(ABSTRACT TRUNCATED AT 250 WORDS)

IL-2 promoter-driven lacZ expression as a monitoring tool for IL-2 expression in primary T cells of transgenic mice

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IL-2 promoter-driven lacZ expression as a monitoring tool for IL-2 expression in primary T cells of transgenic mice