抗原变异可使得多种致病微生物易于逃避宿主免疫应答。表达在感染红细胞表面的恶性疟原虫红细胞表面蛋白1（PfPMP1）与感染红细胞、内皮细胞、树突状细胞以及胎盘的单个或多个受体作用，在黏附及免疫逃避中起关键的作用。每个单倍体基因组var基因家族编码约60种成员，通过启动转录不同的var基因变异体为抗原变异提供了分子基础。

疟原虫var基因转换速率变化导致抗原变异[英]／Paul H, Robert P, Christodoulou Z, et al//Proc Natl Acad Sci U S A

Cell signaling by receptor-tyrosine kinases

The innate immune system in drosophila and mammals senses the invasion of microorganisms using the family of Toll receptors, stimulation of which initiates a range of host defense mechanisms. In drosophila antimicrobial responses rely on two signaling pathways: the Toll pathway and the IMD pathway. In mammals there are at least 10 members of the Toll-like receptor (TLR) family that recognize specific components conserved among microorganisms. Activation of the TLRs leads not only to the induction of inflammatory responses but also to the development of antigen-specific adaptive immunity. The TLR-induced inflammatory response is dependent on a common signaling pathway that is mediated by the adaptor molecule MyD88. However, there is evidence for additional pathways that mediate TLR ligand-specific biological responses.

Toll-like receptors.

Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of cells that expand during cancer, inflammation and infection, and that have a remarkable ability to suppress T-cell responses. These cells constitute a unique component of the immune system that regulates immune responses in healthy individuals and in the context of various diseases. In this Review, we discuss the origin, mechanisms of expansion and suppressive functions of MDSCs, as well as the potential to target these cells for therapeutic benefit.

/pdf/myeloid-derived-suppressor-cells-as-regulators-of-the-immune-4w2mvge6zg.pdf

Myeloid-derived suppressor cells as regulators of the immune system.

Through the study of transcriptional activation in response to interferon alpha (IFN-alpha) and interferon gamma (IFN-gamma), a previously unrecognized direct signal transduction pathway to the nucleus has been uncovered: IFN-receptor interaction at the cell surface leads to the activation of kinases of the Jak family that then phosphorylate substrate proteins called STATs (signal transducers and activators of transcription). The phosphorylated STAT proteins move to the nucleus, bind specific DNA elements, and direct transcription. Recognition of the molecules involved in the IFN-alpha and IFN-gamma pathway has led to discoveries that a number of STAT family members exist and that other polypeptide ligands also use the Jak-STAT molecules in signal transduction.

https://science.sciencemag.org/content/sci/264/5164/1415.full.pdf

Jak-STAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins

NK cell functions were examined in mice with a targeted mutation of the STAT1 gene, an essential mediator of IFN signaling. Mice deficient in STAT1 displayed impaired basal NK cytolytic activity in vitro and were unable to reject transplanted tumors in vivo, despite the presence of normal numbers of NK cells. IL-12 enhanced NK-mediated cytolysis, but poly(I:C) did not, and a similar phenotype occurred in mice lacking IFNalpha receptors. Molecules involved in activation and lytic function of NK cells (granzyme A, granzyme B, perforin, DAP10, and DAP12) were expressed at comparable levels in both wild-type and STAT1(-/-) mice, and serine esterase activity necessary for CTL function was normal, showing that the lytic machinery was intact. NK cells with normal cytolytic activity could be derived from STAT1(-/-) bone marrow progenitors in response to IL-15 in vitro, and enhanced NK lytic activity and normal levels of IFN-gamma were produced in response to IL-12 treatment in vivo. Despite these normal responses to cytokines, STAT1(-/-) mice could not reject the NK-sensitive tumor RMA-S, even following IL-12 treatment in vivo. Whereas in vitro NK cytolysis was also reduced in mice lacking both type I and type II IFN receptors, these mice resisted tumor challenge. These results demonstrate that both IFN-alpha and IFN-gamma are required to maintain NK cell function and define a STAT1-dependent but partially IFN-independent pathway required for NK-mediated antitumor activity.

/pdf/distinct-requirements-for-ifns-and-stat1-in-nk-cell-function-2kps3orz6m.pdf

Distinct Requirements for IFNs and STAT1 in NK Cell Function

Because most commercial potato cultivars were developed in temperate regions, they are adapted, therefore producing the greatest yield under long photoperiods and moderate temperatures. Both heat and salinity stress reduce yield markedly. As potato production moves to areas of the globe where either or both heat and salinity stress are likely to be factors that affect production, our need increases for potato germplasm that can tolerate these adverse conditions. Genetic studies on germplasm variability have revealed species or even cultivars of potato that can resist abiotic stress. The inheritance of abiotic stress resistance is likely to be multigenic, a factor that may limit the utility of transgenic approaches to stress tolerance. However, the development of new methodology, such as association genetics in conjunction with marker-assisted selection, offers promise that stress-tolerant germplasm can be developed as our need increases.

Adaptation of potato to high temperatures and salinity-a review

Histone deacetylase (HDAC) activity, commonly correlated with transcriptional repression, was essential for transcriptional induction of IFN-stimulated genes (ISG). Inhibition of HDAC function led to global impairment of ISG expression, with little effect on basal expression. HDAC function was not required for signal transducer and activator of transcription tyrosine phosphorylation, nuclear translocation, or assembly on chromatin, but it was needed for full activity of the signal transducer and activator of transcription transactivation domain. HDAC function was also required for gene induction driven by the IFN regulatory factor 3 transcription factor activated by virus infection, and it was essential for establishment of an antiviral response against Flaviviridae, Rhabdoviridae, and Picornaviridae. Requirement for HDAC function in transcriptional activation may represent a general mechanism for rapid stimulation of ISG transcription.

https://www.pnas.org/content/pnas/101/26/9578.full.pdf

Induction of interferon-stimulated gene expression and antiviral responses require protein deacetylase activity

Nuclear proteins induced by interferon (IFN) treatment of human cells are capable of forming two specific complexes with DNA fragments containing the IFN-stimulated response element (ISRE). These two complexes, designated B2 and B3, are distinguished by differential migration in gel retardation assays. The factor that forms the B3 complex, termed IFN-stimulated gene factor 3 (ISGF-3), preexists in cells, is activated upon IFN treatment, and appears with kinetics paralleling those for transcriptional activation of IFN-stimulated genes. The factor that forms the B2 complex (ISGF-2) appears following a time lag after IFN treatment during which protein synthesis must occur. By extensive point mutagenesis of the ISREs from two IFN-stimulated promoters (ISG54 and ISG15), we demonstrate that the B2 and B3 complexes are formed by factors binding to the same DNA sequence. Mutations at this site decrease or eliminate transcriptional activation and impair binding of both ISGF-2 and ISGF-3. This analysis has shown that the ISGF-3 binding site is slightly broader than the ISGF-2 binding site, which is completely contained within the sequence necessary both for ISGF-3 binding and for transcriptional activation. The evidence strongly implicates ISGF-3 as the positive transcriptional regulator of IFN-stimulated genes.

Two interferon-induced nuclear factors bind a single promoter element in interferon-stimulated genes

Signal-mediated nuclear import and export proceed through the nuclear pore complex (NPC). Some NPC components, such as the nucleoporins (Nups) Nup98 and Nup96, are also associated with the nuclear interior. Nup98 is a target of the vesicular stomatitis virus (VSV) matrix (M) protein–mediated inhibition of messenger RNA (mRNA) nuclear export. Here, Nup98 and Nup96 were found to be up-regulated by interferon (IFN). M protein–mediated inhibition of mRNA nuclear export was reversed when cells were treated with IFN-γ or transfected with a complementary DNA (cDNA) encoding Nup98 and Nup96. Thus, increased Nup98 and Nup96 expression constitutes an IFN-mediated mechanism that reverses M protein–mediated inhibition of gene expression.

https://science.sciencemag.org/content/sci/295/5559/1523.full.pdf

David E. Levy

Papers

Distinct Requirements for IFNs and STAT1 in NK Cell Function

Adaptation of potato to high temperatures and salinity-a review

Induction of interferon-stimulated gene expression and antiviral responses require protein deacetylase activity

Two interferon-induced nuclear factors bind a single promoter element in interferon-stimulated genes

Role of nucleoporin induction in releasing an mRNA nuclear export block.