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Abstract

Interferon-gamma and interleukin 12 produced by the innate arm of the immune system are important regulators of T helper type 1 (T(H)1) cell development, but signals that negatively regulate their expression remain controversial. Here we show that transforming growth factor-beta (TGF-beta) controlled T(H)1 differentiation through the regulation of interferon-gamma produced by natural killer (NK) cells. Blockade of TGF-beta signaling in NK cells caused the accumulation of a large pool of NK cells secreting copious interferon-gamma, responsible for T(H)1 differentiation and protection from leishmania infection. In contrast, blockade of TGF-beta signaling in dendritic cells did not affect dendritic cell homeostasis or interleukin 12 production, thus indicating a previously undescribed demarcation of the function of TGF-beta in NK cells versus dendritic cells.

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Identification and purification of natural killer cell stimulatory factor (NKSF), a cytokine with multiple biologic effects on human lymphocytes

SC Clark, L Fitz, RM Hewick … (1989)

We have identified and purified a novel cytokine, NK cell stimulatory factor (NKSF), from the cell-free supernatant fluid of the phorbol diester-induced EBV-transformed human B lymphoblastoid cell line RPMI 8866. NKSF activity is mostly associated to a 70-kD anionic glycoprotein. The purified 70-kD protein, isolated from an SDS-PAGE gel, yields upon reduction two small species of molecular masses of 40 and 35 kD, suggesting that this cytokine is a heterodimer. When added to human PBL, purified NKSF preparations induce IFN-gamma production and synergize with rIL-2 in this activity, augment the NK cell-mediated cytotoxicity of PBL preparations against both NK-sensitive and NK- resistant target cell lines, and enhance the mitogenic response of T cells to mitogenic lectins and phorbol diesters. The three activities remain associated through different purification steps resulting in a 9,200-fold purification, and purified NKSF mediates the three biological activities at concentrations in the range of 0.1-10 pM. These data strongly suggest that the same molecule mediates these three activities, although the presence of traces of contaminant peptides even in the most purified NKSF preparations does not allow us to exclude the possibility that distinct biologically active molecules have been co-purified. The absence of other known cytokines in the purified NKSF preparations, the unusual molecular conformation of NKSF, the high specific activity of the purified protein, and the spectrum of biological activities distinguish NKSF from other previously described cytokines.

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Abrogation of TGFbeta signaling in T cells leads to spontaneous T cell differentiation and autoimmune disease.

L Gorelik, R A Flavell (2000)

Targeted mutation of TGFbeta1 in mice demonstrated that TGFbeta1 is one of the key negative regulators of immune homeostasis, as its absence leads to activation of a self-targeted immune response. Nevertheless, because of the highly pleiotropic properties of TGFbeta and the presence of TGFbeta receptors on most cell types, its biologic role in the regulation of immune homeostasis is not yet understood. To limit the consequences of TGFbeta effects to a single cell type, we developed a transgenic approach to abrogate the TGFbeta response in key immune cells. Specifically, we expressed a dominant-negative TGFbeta receptor type II under a T cell-specific promoter and created a mouse model where signaling by TGFbeta is blocked specifically in T cells. Using this transgenic model, we show that T cell homeostasis requires TGFbeta signaling in T cells.

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A mutation in the interferon-gamma-receptor gene and susceptibility to mycobacterial infection.

M Newport, C Huxley, S. Huston … (1996)

Genetic differences in immune responses may affect susceptibility to mycobacterial infection, but no specific genes have been implicated in humans. We studied four children who had an unexplained genetic susceptibility to mycobacterial infection and who appeared to have inherited the same recessive mutation from a common ancestor. We used microsatellite analysis, immunofluorescence studies, and sequence analysis to study the affected patients, unaffected family members, and normal controls. A genome search using microsatellite markers identified a region on chromosome 6q in which the affected children were all homozygous for eight markers. The gene for interferon-gamma receptor 1 maps to this region. Immunofluorescence studies showed that the receptor was absent on leukocytes from the affected children. Sequence analysis of complementary DNA for the gene for interferon-gamma receptor 1 revealed a point mutation at nucleotide 395 that introduces a stop codon and results in a truncated protein that lacks the transmembrane and cytoplasmic domains. Four children with severe mycobacterial infections had a mutation in the gene for interferon-gamma receptor 1 that leads to the absence of receptors on cell surfaces and a functional defect in the up-regulation of tumor necrosis factor alpha by macrophages in response to interferon-gamma. The interferon-gamma pathway is important in the response to intracellular pathogens such as mycobacteria.

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PubMed ID:: 15852008

DOI:: 10.1038/ni1197

ScienceOpen disciplines: Chemistry

Keywords: Animals,Antigens, CD11c,genetics,metabolism,Base Sequence,Cell Differentiation,DNA, Recombinant,Dendritic Cells,immunology,Humans,Immunity, Innate,In Vitro Techniques,Interferon-gamma,biosynthesis,Killer Cells, Natural,Leishmania major,pathogenicity,Mice,Mice, Inbred BALB C,Mice, Inbred C57BL,Mice, Transgenic,Protein-Serine-Threonine Kinases,Receptors, Transforming Growth Factor beta,Recombinant Proteins,pharmacology,Signal Transduction,Th1 Cells,cytology,Transforming Growth Factor beta

Transforming growth factor-beta controls T helper type 1 cell development through regulation of natural killer cell interferon-gamma.

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Abstract

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Most cited references 29

Identification and purification of natural killer cell stimulatory factor (NKSF), a cytokine with multiple biologic effects on human lymphocytes

Abrogation of TGFbeta signaling in T cells leads to spontaneous T cell differentiation and autoimmune disease.

A mutation in the interferon-gamma-receptor gene and susceptibility to mycobacterial infection.

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