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

Mass cytometric analysis reveals a remarkable and unanticipated degree of phenotypic heterogeneity among human peripheral blood natural killer cells.

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Of snowflakes and natural killer cell subsets

Nucleic acids encoding various monocyte cell proteins from a primate, reagents related thereto, including specific antibodies, and purified proteins are described. Methods of using said reagents and related diagnostic kits are also provided.

Isolated mammalian monocyte cell genes; related reagents

Cytolysis by NK cells that possess the NKB1 killer cell inhibitory receptor is inhibited by target cell expression of Bw4+ HLA-B molecules. The inhibitory effect can be prevented by addition of mAbs which block recognition of class I molecules by NKB1. The epitopes recognized by two anti-class I mAbs, DX15 and DX16, which inhibit the interaction of NKB1 with class I have been characterized. Binding of DX15 and DX16 to class I allotypes was investigated by flow cytometric analysis of transfected cell lines which express just one HLA-A, B, or C allele, and by immunoprecipitation of class I molecules from HLA typed B-lymphoblastoid cell lines, followed by isoelectric focusing. The DX16 mAb recognizes class I allotypes which possess alanine at position 71 of the alpha 1 helix, and therefore has a specificity resembling that of the ME1 mAb but with broader specificity. Class I recognition by DX15 is affected by polymorphisms of the C-terminal part of the alpha 1 helix, and the N-terminal part of the alpha 2 helix. DX15 thus appears to recognize a complex epitope near the end of the peptide binding groove which may be conformationally determined. Both antibodies are as effective as the anti-NKB1 mAb (DX9) in preventing class I recognition by the NKB1 receptor. DX16 also blocked recognition by a B*0702 allospecific CTL clone, whereas DX15 did not.

Specificity of two anti‐class IHLA monoclonal antibodies that block class I recognition by the NKB1 killer cell inhibitory receptor

Under different circumstances, tumors can inhibit or activate macrophage (Mphi) effector functions. We studied the mechanisms of tumor-Mphi interactions leading to Mphi activation. The results show that L5178Y mouse T cell lymphoma cells can prime naive mouse Mphi to subsequent LPS stimulation, resulting in increased NO production and antilymphoma effects in vitro. L5178Y cells, but not naive splenocytes, primed Mphi to ligation of TLR4 but not TLR9. L5178Y-primed Mphi incubated with LPS showed down-regulation of CD40 and up-regulation of NKG2D expression. Although L5178Y T cell lymphoma cells primed naive mouse Mphi, several other mouse and human cells lines failed to prime mouse Mphi. Neither L5178Y-conditioned supernatants nor coculture of Mphi and L5178Y cells in Transwells resulted in priming, indicating that direct L5178Y cell-Mphi contact was needed. Several receptor-ligand pairs are reciprocally expressed on Mphi and L5178Y cell membranes and can be potentially involved in Mphi priming. Of these, the CD40-CD154 pair played the most important role, as blocking the interaction of these molecules substantially reduced in vitro Mphi priming. Furthermore, simultaneous blocking of interactions between CD40-CD154, NKG2D-H60, and CD18-ICAM-1/2 led to complete abrogation of Mphi-mediated NO secretion and complete inhibition of Mphi-mediated tumor cell cytostasis. The priming of Mphi to LPS with L5178Y cells was also observed in vivo. These results suggest that contact with certain tumor cells via CD40, NKG2D, and CD18 molecules on the Mphi may facilitate Mphi-mediated antitumor immune surveillance.

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Naive mouse macrophages become activated following recognition of L5178Y lymphoma cells via concurrent ligation of CD40, NKG2D, and CD18 molecules.

Natural killer (NK) cells are key mediators in the control of cytomegalovirus infection. Here, we show that Epstein-Barr virus-induced 3 (EBI3) is expressed by human NK cells after NKG2D or IL-12 plus IL-18 stimulation and by mouse NK cells during mouse cytomegalovirus (MCMV) infection. The induction of EBI3 protein expression in mouse NK cells is a late activation event. Thus, early activation events of NK cells, such as IFNγ production and CD69 expression, were not affected in EBI3-deficient (Ebi3-/- ) C57BL/6 (B6) mice during MCMV infection. Furthermore, comparable levels of early viral replication in spleen and liver were observed in MCMV-infected Ebi3-/- and wild-type (WT) B6 mice. Interestingly, the viral load in salivary glands and oral lavage was strongly decreased in the MCMV-infected Ebi3-/- B6 mice, suggesting that EBI3 plays a role in the establishment of MCMV latency. We detected a decrease in the sustained IL-10 production by NK cells and lower serum levels of IL-10 in the MCMV-infected Ebi3-/- B6 mice. Furthermore, we observed an increase in dendritic cell maturation markers and an increase in activated CD8+ T cells. Thus, EBI3 dampens the immune response against MCMV infection, resulting in prolonged viral persistence.

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Lewis L. Lanier

Papers

Of snowflakes and natural killer cell subsets

Isolated mammalian monocyte cell genes; related reagents

Specificity of two anti‐class IHLA monoclonal antibodies that block class I recognition by the NKB1 killer cell inhibitory receptor

Naive mouse macrophages become activated following recognition of L5178Y lymphoma cells via concurrent ligation of CD40, NKG2D, and CD18 molecules.

EBI3 regulates the NK cell response to mouse cytomegalovirus infection