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

B and T lymphocytes are the mediators of immunity, but their function is under the control of dendritic cells. Dendritic cells in the periphery capture and process antigens, express lymphocyte co-stimulatory molecules, migrate to lymphoid organs and secrete cytokines to initiate immune responses. They not only activate lymphocytes, they also tolerize T cells to antigens that are innate to the body (self-antigens), thereby minimizing autoimmune reactions. Once a neglected cell type, dendritic cells can now be readily obtained in sufficient quantities to allow molecular and cell biological analysis. With knowledge comes the realization that these cells are a powerful tool for manipulating the immune system.

Dendritic cells and the control of immunity

Immune checkpoints refer to the plethora of inhibitory pathways that are crucial to maintaining self-tolerance. Tumour cells induce immune checkpoints to evade immunosurveillance. This Review discusses the progress in targeting immune checkpoints, the considerations for combinatorial therapy and the potential for additional immune-checkpoint targets.

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The blockade of immune checkpoints in cancer immunotherapy

Comprehensive Integration of Single-Cell Data.

Dendritic cells (DCs) are antigen-presenting cells with a unique ability to induce primary immune responses. DCs capture and transfer information from the outside world to the cells of the adaptive immune system. DCs are not only critical for the induction of primary immune responses, but may also be important for the induction of immunological tolerance, as well as for the regulation of the type of T cell-mediated immune response. Although our understanding of DC biology is still in its infancy, we are now beginning to use DC-based immunotherapy protocols to elicit immunity against cancer and infectious diseases.

Immunobiology of Dendritic Cells

In 1986, Joe Phillips and I published a paper in The Journal of Immunology identifying the CD56bright+, CD16−, and CD56+, CD16+ NK cell subsets in humans that began, “Natural killer (NK) cells are a population of lymphocytes derived from an unimmunized host that lyse certain tumor cell lines and

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Missing self, NK cells, and The White Album.

Monocytes constitutively express Fc receptor (FcR) for IgG type I (CD64) and type II (CD32), but not type III (CD16). Prior studies have indicated that in vitro culture of monocytes results in spontaneous induction of CD16, but this phenomenon has been variable and the mechanism unexplained. Here, we demonstrate that activated platelets are responsible for induction of CD16 on monocytes, as a consequence of TGF-beta release. Local release of TGF-beta by activated platelets at sites of tissue damage may induce CD16 on infiltrating or resident monocytes that in turn facilitate the function of these effector cells. The FcR on these CD16+ monocytes is functionally competent, and enables the monocytes to kill murine anti-CD16 hybridoma cells. CD16 expressed on platelet-activated monocytes is structurally similar to the transmembrane-anchored CD16-II polypeptide expressed on natural killer (NK) cells. However, whereas CD16-II on NK cells is co-associated with CD3 zeta, we were unable to detect CD3 zeta transcript or protein in monocytes. Transcripts for the gamma subunit of the high-affinity IgE FcR (Fc epsilon RI-gamma) were detected in monocytes, and presumably gamma proteins are co-associated with CD16-II in these cells. Nucleotide sequence analysis of Fc epsilon RI-gamma cDNA derived from both NK cells and cultured monocytes indicated identity with the structure previously cloned from basophils. Since CD16+ monocytes can kill anti-CD16 hybridoma cell targets in the absence of CD3 zeta, these results indicate that CD3 zeta is not essential for signal transduction in CD16-II-mediated cytotoxicity.

Platelet-induced expression of FcγRIII (CD16) on human monocytes

T cell activation represents a balance between positive and negative signals delivered via distinct cell surface molecules. Many cytoplasmic protein tyrosine phosphatases are involved in regulating cellular responses by antagonizing the action of protein tyrosine kinases. CD148 is a receptor-type protein tyrosine phosphatase expressed by all human mononuclear cells. We have investigated the effect of CD148 on TCR-mediated activation of human T cells. Overexpression of wild-type, but not a phosphatase-deficient, CD148 in Jurkat T cells inhibited TCR-mediated activation, evidenced by reduced expression of the early activation Ag CD69, inhibition of tyrosine phosphorylation of many intracellular proteins including the critical protein tyrosine kinase ZAP-70, and impairment of mitogen-activated protein kinase activation. Taken together, these results suggest that CD148 is an important phosphatase involved in negatively regulating the proximal signaling events during activation of Ag-specific T cells.

Negative regulation of human T cell activation by the receptor-type protein tyrosine phosphatase CD148.

Immunotherapy represents one of the major breakthroughs in the treatment of cancer patients. Current therapies focus on harnessing the adaptive immune system, with great success achieved by interfering with immune checkpoints to unleash antitumor CD8+ T cell responses. There is emerging evidence that cancers develop multiple strategies to escape CD8+ T cell recognition. These tumors, however, can be preferentially attacked by natural killer (NK) cells. NK cells are innate lymphocytes that express activating receptors, including the NK group 2D (NKG2D) receptor, which recognize ligands displayed on the surface of tumor cells and pathogen-infected cells. On page 1537 of this issue, Ferrari de Andrade et al. ( 1 ) present an elegant approach to improve NK cell recognition of tumor cells, extending the range of immunotherapies beyond T cells.

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Natural killers join the fight against cancer

Natural killer (NK) cells are innate lymphoid cells that have been increasingly recognised as important in lung allograft tolerance and immune defence. These cells evolved to recognise alterations in self through a diverse set of germline-encoded activating and inhibitory receptors and display a broad range of effector functions that play important roles in responding to infections, malignancies and allogeneic tissue. Here, we review NK cells, their diverse receptors and the mechanisms through which NK cells are postulated to mediate important lung transplant clinical outcomes. NK cells can promote tolerance, such as through the depletion of donor antigen-presenting cells. Alternatively, these cells can drive rejection through cytotoxic effects on allograft tissue recognised as 'non-self' or 'stressed', via killer cell immunoglobulin-like receptor (KIR) or NKG2D receptor ligation, respectively. NK cells likely mediate complement-independent antibody-mediated rejection of allografts though CD16A Fc receptor-dependent activation induced by graft-specific antibodies. Finally, NK cells play an important role in response to infections, particularly by mediating cytomegalovirus infection through the CD94/NKG2C receptor. Despite these sometimes-conflicting effects on allograft function, enumeration of NK cells may have an important role in diagnosing allograft dysfunction. While the effects of immunosuppression agents on NK cells may currently be largely unintentional, further understanding of NK cell biology in lung allograft recipients may allow these cells to serve as biomarkers of graft injury and as therapeutic targets.

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Lewis L. Lanier

Papers

Missing self, NK cells, and The White Album.

Platelet-induced expression of FcγRIII (CD16) on human monocytes

Negative regulation of human T cell activation by the receptor-type protein tyrosine phosphatase CD148.

Natural killers join the fight against cancer

Natural killer cells in lung transplantation.