Primary immune surveillance: some like it hot

The thermal element of fever has been found to be beneficial in models of infectious disease. The contributions of fever-range temperatures to the efficacy of the adaptive immune response have only begun to be delineated. There is accumulating evidence that fever-range thermal stress bolsters primary immune surveillance of lymph nodes and Peyer patches by augmenting lymphocyte extravasation across specialized vessels termed high endothelial venules. Molecular mechanisms have recently come to light by which the thermal component of fever alone may promote lymphocyte trafficking, and thereby the probability of mounting a defense against microbial infection. Acquired knowledge of the molecular changes associated with thermal stress may allow for the development of novel therapies for a variety of disease processes.

The Yin-Yang of tumor-associated macrophages in neoplastic progression and immune surveillance

Summary: An intrinsic (oncogene-driven) pathway and an extrinsic (microenvironment-driven) pathway connect inflammatory reactions and cancer. M2-polarized tumor-associated macrophages and the related myeloid-derived suppressor cells are key prototypic components of smoldering inflammation driving neoplastic progression. However, mononuclear phagocytes can exert anti-tumor activity by killing tumor cells and eliciting tissue disruptive reactions (M1), a likely scenario in the early phases of carcinogenesis of immunogenic tumors and following therapeutic intervention. Shifting the macrophage balance represents a viable therapeutic target. Herein, the 'macrophage balance' is discussed in the context of the apparent paradox of tumor promotion by innate immunity-driven inflammation and the seemingly opposed tumor surveillance by adaptive immune responses.     

NKG2D及其配体在白血病免疫监视中的作用

NKG2D是免疫细胞表面的激活性受体,在机体的抗肿瘤免疫、抗感染免疫以及自身免疫病的发生中发挥重要作用。NKG2D识别肿瘤细胞表面的配体,激活效应细胞,产生有效的抗肿瘤免疫应答,是肿瘤免疫监视机制之一。近来研究发现白血病细胞表达多种NKG2D配体,参与白血病的免疫监视。本文就NKG2D及其配体对白血病免疫监视和免疫逃逸的作用作一综述。     

TGF-β: a mobile purveyor of immune privilege

Summary:  Functionally barricaded immune responses or sites of immune privilege are no longer considered dependent on specific anatomical considerations, but rather, they can develop in any location where immunoregulatory cells congregate and express or release products capable of deviating the host response to foreign antigens. Among the pivotal molecules involved in orchestrating these ectopic sites of immune suppression is transforming growth factor-β (TGF-β), a secreted and cell-associated polypeptide with a multiplicity of actions in innate and adaptive immunity. While beneficial in initiating and controlling immune responses and maintaining immune homeostasis, immunosuppressive pathways mediated by TGF-β may obscure immune surveillance mechanisms, resulting in failure to recognize or respond adequately to self, foreign, or tumor-associated antigens. CD4⁺CD25⁺Foxp3⁺ regulatory T cells represent a dominant purveyor of TGF-β-mediated suppression and are found in infiltrating tumors and other sites of immune privilege, where they influence CD8⁺ T cells; CD4⁺ T-helper (Th)1, Th2, and Th17 cells; natural killer cells; and cells of myeloid lineage to choreograph and/or muck up host defense. Defining the cellular sources, mechanisms of action, and networking that distinguish the dynamic establishment of localized immune privilege is vital for developing strategic approaches to diminish or to embellish these tolerogenic events for therapeutic benefit.     

Dichotomy of Notch signalling in regulating tumour immune surveillance

Notch signalling is an evolutionarily conserved multifaceted pathway that controls diverse cellular processes. Its role in regulating development and tissue homeostasis is well established. Aberrant activation of the Notch pathway has been implicated in the initiation and progression of many types of cancers. However, although in some cancers Notch signalling acts as a tumour‐promoter, in others it is reported to suppress tumour growth and progression. Accumulating evidence suggests the involvement of both the innate and adaptive immune system in the development of various tumours. Currently, extensive studies on investigating the effects of Notch signalling in tumour immune surveillance are being carried out. Interestingly, recent literature shows how the changing expression of Notch genes in different T cell subsets like CD4 and CD8 helps in controlling anti‐tumour immune responses. In this review, we discuss in depth the roles of Notch signalling molecules and different immune cells in the context of the tumour microenvironment. We also outline how current knowledge can be exploited to develop novel therapies in order to control the propagation of cancer stem cells.     

The reversal immune surveillance hypothesis.

The proposed reveral immune surveillance hypothesis is based on the identification primarily of self and secondarily of foreignness, unlike the original hypothesis that is based on the identification of foreignness per se. The proposed system is considered to have evolved from the invertebrates through to the vertebrates to become more complex in the mammals, and involves the identification of cell types by lymphocytes through the cell type surface pattern and major histocompatibility antigens. The identification of self and associated foreignness by the immune system is required for the regulation of cell differentiation and replication, and because of this design, the ability of the immune system to destroy foreignness can be regarded as a natural consequence. The reversal immune surveillance hypothesis explains why spontaneously occurring tumours may not be antigenic, in the sense of eliciting their own destruction, and is consistent with the destruction of tumour cells that display significant amounts of viral antigens or gross antigenic changes induced by carcinogenic agents. It is also able to explain the stimulation and inhibition of tumour development.     

Rat colon carcinoma cells that survived systemic immune surveillance are less sensitive to NK-cell mediated apoptosis

In order to form distant metastases, cells from the primary tumor have to detach, enter the blood- or lymph-compartment and escape immune surveillance. Here, we describe the selection of rat colon carcinoma cell lines (CC531s-m1 and CC531s-m2) that escaped from systemic immune surveillance; CC531s cells were injected into the v. jugularis of Wag/Rij rats, after three weeks the lung tumors were isolated, the tumor cells were cultured, characterized and injected again. The m1- and m2-cell lines were less susceptible for killing by syngeneic NK cells. Further characterization of this cell line showed a decreased sensitivity towards TRAIL- and CD95L-, but not to granzyme B-mediated apoptosis. In the m1- and m2-cells log-phase growth started earlier as compared to the parental cell line, whereas no changes were found in anchorage-dependent or anchorage-independent growth. After subcapsular injection of the m2-cell line into the liver of rats much more lung metastases were formed in comparison to injection of the parental cell line. In conclusion, the results suggest that the resistance of the m1- and m2-cells to NK cell-mediated apoptosis was associated with their capability to survive systemic immune surveillance and form metastases in vivo.     

肿瘤基因疫苗的研究进展

肿瘤基因疫苗是肿瘤主动特异性免疫治疗的核心.本文就肿瘤基因疫苗的构建、靶基因的选择以及免疫效应等方面的研究进展作一综述.     

Mechanism of tumor cells escaping from immune surveillance of NK cells

Abstract

Natural killer (NK) cells play an important role in anti-tumor and anti-infection, and perform their immune surveillance function in various ways. However, no matter what kind of cancer, the functional activity of NK cells in the tumor microenvironment (TME) is suppressed. Understanding the relationship between tumor cells and NK cells is very critical for tumor immunotherapy. This review discusses the mechanism of tumor cells escaping the immune surveillance of NK cells. These include a variety of factors that inhibit the activity of NK cells, an imbalance of activating receptors and inhibiting receptors on NK cells, abnormal binding of receptors and ligands, cross-talk of surrounding cell groups and NK cells in the TME, and other factors that affect NK cell activity. An understanding of these factors is necessary to provide new treatment strategies for tumor immunotherapy.     

Effective and selective immune surveillance of the brain by MHC class I-restricted cytotoxic T lymphocytes

Cytotoxic CD8(+) T cells are abundantly present in human virus-induced or putative autoimmune diseases of the central nervous system (CNS). Their direct role in the induction of inflammatory brain damage is, however, poorly understood. We have studied CD8(+) T cell-mediated brain inflammation by transferring MHC class I-restricted hemagglutinin (HA)-reactive T cells from a TCR transgenic mouse line into transgenic mice, which express HA in astrocytes. We show that activated CD8(+) T cells alone can induce monophasic brain inflammation in immunocompetent recipient animals. Similar to previous studies, involving transfer of CD4(+) cells, brain inflammation peaks after 5-7 days and then declines. The pathology of brain inflammation, however, differs fundamentally from that induced by CD4(+) cells. The inflammatory reaction is dominated by T cells and activated microglia in the virtual absence of hematogenous macrophages. This is associated with exquisitely specific destruction of antigen-containing astrocytes in the absence of any bystander damage of myelin, oligodendrocytes or neurons. Furthermore, in contrast to CD4(+) T cells, some CD8(+) cells accumulate in the brain and activate microglia in recipient animals, even in the absence of the specific antigen in the CNS. These data indicate that CD8(+) T cells are prime candidates for immune surveillance of the CNS.     

The response in old mice: positive and negative immune memory after priming in early age

To analyze the effect of age in both B and T cell compartments of the immune system, we have studied the anti-dextran (Dx) B512 humoral immune response in aged C57BL/6 mice. We have used Dx in its native form, which induces a thymus-independent (TI) response, or conjugated to chicken serum albumin (CSA), which induces a thymus-dependent (TD) response. We have also analyzed the adjuvant effect of cholera toxin (CT) in both types of responses. Our results show that the B cell compartment is not greatly affected by age as demonstrated in the TI responses and that CT is a powerful adjuvant despite the age of the animals. However, we found a severe age-associated impairment of TD responses. We conclude that the first antigenic challenge deeply influences further antigenic responses in a positive or negative manner. Priming in early life with native Dx (TI) inhibited late TD responses in aged mice, even when the primary immunization had occurred a long time ago. This negative memory affects posterior TD responses both in the quantity and in the affinity of the response. However, immunization at an early age with TD priming (CSA-Dx) provoked a long-lasting immune memory that abolished in part the age-associated impairment of the response. Our results suggest that protocols of vaccination with TI antigens may not be a convenient strategy, because the development of further optimal immune responses to the same antigen can be impaired.     

乙型肝炎病毒基因疫苗诱导小鼠产生特异免疫应答

构建编码乙型肝炎病毒（ＨＢＶ）表面蛋白Ｓ的重组质粒ｐＣＲ３．１－Ｓ。将之直接肌肉注射Ｂａｌｂ／ｃ小鼠,观察小鼠ＨＢＶ特异的免疫应答。以ＥＬＩＳＡ法检测小鼠血清,＾３Ｈ－ＴｄＲ掺入法测定淋巴细胞增殖,＾５１Ｃｒ４ｈ释放法检测淋巴细胞杀伤功能。结果表明,与空载体对照组相比较,基因疫苗诱发小鼠产生良了的抗ＨＢｓ反应及ＨＢＶ特异的细胞免疫应答（Ｐ〈０．０５）,提示基因疫苗ｐＣＲ３．１－Ｓ有可能成为控制ＨＢ     

Immunoinformatics: an overview of computational tools and techniques for understanding immune function

In recent years, there has been a rapid expansion in the application of information technology to biological data. Although the use of information science techniques is less common for the discipline of immunology, this field has seen great strides in recent years. This review addresses why in silico modeling is needed in immunology research, highlights some of the major areas of research and suggests what may be important for the future of immunoinformatics.     

The role of CD11c(+) hepatic dendritic cells in the induction of innate immune responses

The role of the liver in the initiation and maintenance of tolerance is a critical immune function that involves multiple lineages of immune cells. Included within these populations are liver dendritic cells (DCs). Although there has been significant work on the phenotypic and functional roles of splenic and bone marrow dendritic cells, as well as their subsets, comparable studies in liver have often been difficult. To address this issue we have isolated, from C57BL/6 mice, relatively pure populations of DCs and compared phenotype and function to the data from spleen using flow cytometry, cell sorter assisted purification and culture, morphology by cytospin and May-Giemsa staining, cell cycle progression, antigen uptake, cytokine production and allo-activation potential. natural killer (NK)1.1(-)CD11c(+) liver DC subsets (conventional DCs, T cell receptor (TcR)beta(-)NK1.1(-)CD11c(+)B220(-) and plasmacytoid DCs, TcRbeta(-)NK1.1(-)CD11c(+)B220(+)) efficiently endocytose dextran and produce significant levels of tumour necrosis factor (TNF)-alpha, interleukin (IL)-6 and IL-12 p40 in response to Toll-like receptor (TLR) ligands, with responses higher than splenic DCs. There is also a differential capability of hepatic DCs to respond to innate signals. Indeed, CD11c(+) hepatic DCs have a greater capacity to respond to innate stimulation but are less capable of inducing CpG activated-allogeneic T cells. These data suggest that hepatic dendritic cells function as a critical bridge between innate and adaptive immunity and are capable of inducing stronger innate responses with a lower capacity for allo-stimulation than splenic dendritic cells. These properties of liver dendritic cells contribute to their unique role in the induction of tolerance.