Natural killer (NK) T cells are a lymphocyte subset with a distinct surface phenotype, an invariant T cell receptor (TCR), and reactivity to CD1. Here we show that mouse NK T cells can recognize human CD1d as well as mouse CD1, and human NK T cells also recognize both CD1 homologues. The unprecedented degree of conservation of this T cell recognition system suggests that it is fundamentally important. Mouse or human CD1 molecules can present the glycolipid α-galactosylceramide (α-GalCer) to NK T cells from either species. Human T cells, preselected for invariant Vα24 TCR expression, uniformly recognize α-GalCer presented by either human CD1d or mouse CD1. In addition, culture of human peripheral blood cells with α-GalCer led to the dramatic expansion of NK T cells with an invariant (Vα24+) TCR and the release of large amounts of cytokines. Because invariant Vα14+ and Vα24+ NK T cells have been implicated both in the control of autoimmune disease and the response to tumors, our data suggest that α-GalCer could be a useful agent for modulating human immune responses by activation of the highly conserved NK T cell subset.
Peripheral tolerance to tumor antigens (Ags) is a major hurdle for antitumor immunity. Draining lymph nodes are considered the privileged sites for Ag presentation to T cells and for the onset of peripheral tolerance. Here, we show that the spleen is fundamentally important for tumor-induced tolerance. Splenectomy restores lymphocyte function and induces tumor regression when coupled with immunotherapy. Splenic CD11b(+)Gr-1(int)Ly6C(hi) cells, mostly comprising proliferating CCR2(+)-inflammatory monocytes with features of myeloid progenitors, expand in the marginal zone of the spleen. Here, they alter the normal tissue cytoarchitecture and closely associate with memory CD8(+) T cells, cross-presenting tumor Ags and causing their tolerization. Because of its high proliferative potential, this myeloid cell subset is also susceptible to low-dose chemotherapy, which can be exploited as an adjuvant to passive immunotherapy. CCL2 serum levels in cancer patients are directly related to the accumulation of immature myeloid cells and are predictive for overall survival in patients who develop a multipeptide response to cancer vaccines.
Although tremendous progress has been made toward identifying factors that regulate nucleosome structure and positioning, the mechanisms that regulate higher-order chromatin structure remain poorly understood. Recent studies suggest that the ISWI chromatin-remodeling factor plays a key role in this process by promoting the assembly of chromatin containing histone H1. To test this hypothesis, we investigated the function of H1 in Drosophila. The association of H1 with salivary gland polytene chromosomes is regulated by a dynamic, ATP-dependent process. Reducing cellular ATP levels triggers the dissociation of H1 from polytene chromosomes and causes chromosome defects similar to those resulting from the loss of ISWI function. H1 knockdown causes even more severe defects in chromosome structure and a reduction in nucleosome repeat length, presumably due to the failure to incorporate H1 during replication-dependent chromatin assembly. Our findings suggest that ISWI regulates higher-order chromatin structure by modulating the interaction of H1 with interphase chromosomes. T HE packaging of DNA into chromatin is critical for the organization and regulation of eukaryotic genes. The basic unit of chromatin structure-the nucleosome--can be packaged in 30-nm fibers and increasingly compact structures. Higher-order chromatin structure influences many aspects of gene expression, including transcription factor binding, enhancer-promoter interactions, and the organization of chromatin into functional domains. Histone H1 and related linker histones are important determinants of higher-order chromatin structure. These abundant, basic proteins share a common structure consisting of a globular winged helix DNA-binding domain flanked by a short N-terminal segment and a C-terminal domain of 100 amino acids (Brown 2003). The winged helix domain of H1 binds the nucleosome near the site of DNA entry and exit; the flanking domains interact with core and linker DNA to promote the formation and packaging of 30-nm fibers in vitro (Robinson and Rhodes 2006;Maier et al. 2008).
Nucleosome-remodelling factors containing the ATPase ISWI, such as ACF, render DNA in chromatin accessible by promoting the sliding of histone octamers. Although the ATP-dependent repositioning of mononucleosomes is readily observable in vitro, it is unclear to which extent nucleosomes can be moved in physiological chromatin, where neighbouring nucleosomes, linker histones and the folding of the nucleosomal array restrict mobility. We assembled arrays consisting of 12 nucleosomes or 12 chromatosomes (nucleosomes plus linker histone) from defined components and subjected them to remodelling by ACF or the ATPase CHD1. Both factors increased the access to DNA in nucleosome arrays. ACF, but not CHD1, catalysed profound movements of nucleosomes throughout the array, suggesting different remodelling mechanisms. Linker histones inhibited remodelling by CHD1. Surprisingly, ACF catalysed significant repositioning of entire chromatosomes in chromatin containing saturating levels of linker histone H1. H1 inhibited the ATP-dependent generation of DNA accessibility by only about 50%. This first demonstration of catalysed chromatosome movements suggests that the bulk of interphase euchromatin may be rendered dynamic by dedicated nucleosome-remodelling factors.
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