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

The discovery of Toll-like receptors (TLRs) as components that recognize conserved structures in pathogens has greatly advanced understanding of how the body senses pathogen invasion, triggers innate immune responses and primes antigen-specific adaptive immunity. Although TLRs are critical for host defense, it has become apparent that loss of negative regulation of TLR signaling, as well as recognition of self molecules by TLRs, are strongly associated with the pathogenesis of inflammatory and autoimmune diseases. Furthermore, it is now clear that the interaction between TLRs and recently identified cytosolic innate immune sensors is crucial for mounting effective immune responses. Here we describe the recent advances that have been made by research into the role of TLR biology in host defense and disease.

/pdf/the-role-of-pattern-recognition-receptors-in-innate-immunity-39y77tlxza.pdf

The role of pattern-recognition receptors in innate immunity: update on Toll-like receptors

Cancers develop in complex tissue environments, which they depend on for sustained growth, invasion and metastasis. Unlike tumor cells, stromal cell types within the tumor microenvironment (TME) are genetically stable and thus represent an attractive therapeutic target with reduced risk of resistance and tumor recurrence. However, specifically disrupting the pro-tumorigenic TME is a challenging undertaking, as the TME has diverse capacities to induce both beneficial and adverse consequences for tumorigenesis. Furthermore, many studies have shown that the microenvironment is capable of normalizing tumor cells, suggesting that re-education of stromal cells, rather than targeted ablation per se, may be an effective strategy for treating cancer. Here we discuss the paradoxical roles of the TME during specific stages of cancer progression and metastasis, as well as recent therapeutic attempts to re-educate stromal cells within the TME to have anti-tumorigenic effects.

/pdf/microenvironmental-regulation-of-tumor-progression-and-4528oymlw6.pdf

Microenvironmental regulation of tumor progression and metastasis.

PD-1 is an immunoinhibitory receptor expressed by activated T cells, B cells, and myeloid cells. Mice deficient in PD-1 exhibit a breakdown of peripheral tolerance and demonstrate multiple autoimmune features. We report here that the ligand of PD-1 (PD-L1) is a member of the B7 gene family. Engagement of PD-1 by PD-L1 leads to the inhibition of T cell receptor-mediated lymphocyte proliferation and cytokine secretion. In addition, PD-1 signaling can inhibit at least suboptimal levels of CD28-mediated costimulation. PD-L1 is expressed by antigen-presenting cells, including human peripheral blood monocytes stimulated with interferon gamma, and activated human and murine dendritic cells. In addition, PD-L1 is expressed in nonlymphoid tissues such as heart and lung. The relative levels of inhibitory PD-L1 and costimulatory B7-1/B7-2 signals on antigen-presenting cells may determine the extent of T cell activation and consequently the threshold between tolerance and autoimmunity. PD-L1 expression on nonlymphoid tissues and its potential interaction with PD-1 may subsequently determine the extent of immune responses at sites of inflammation.

/pdf/engagement-of-the-pd-1-immunoinhibitory-receptor-by-a-novel-2cb02kpkk5.pdf

Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation.

Fas ligand (FasL), a cell surface molecule belonging to the tumor necrosis factor family, binds to its receptor Fas, thus inducing apoptosis of Fas-bearing cells. Various cells express Fas, whereas FasL is expressed predominantly in activated T cells. In the immune system, Fas and FasL are involved in down-regulation of immune reactions as well as in T cell-mediated cytotoxicity. Malfunction of the Fas system causes lymphoproliferative disorders and accelerates autoimmune diseases, whereas its exacerbation may cause tissue destruction.

https://science.sciencemag.org/content/sci/267/5203/1449.full.pdf

The Fas Death Factor

Inhibitory and activatory receptors for MHC class I molecules

Genetic Dissection of the Transducing Subunits of the T‐Cell Antigen Receptor

Erratum and corrigendum: Innate and adaptive immunity: specificities and signaling hierarchies revisited

/pdf/erratum-and-corrigendum-innate-and-adaptive-immunity-4xwij686ef.pdf

/pdf/structure-et-fonction-du-complexe-cd16-z-g-des-cellules-nk-30qbv5zx78.pdf

Structure et fonction du complexe CD16 :ζ :γ des cellules NK

Les phosphatases regroupent un ensemble d'enzymes qui different dans leurs localisations cellulaires, leurs specificites de substrat ou leurs roles dans l'homeostasie cellulaire. Ainsi, on retrouve des phosphatases transmembranaires impliquees aussi bien dans l'adherence, la differenciation et la migration cellulaire que dans la transmission des signaux. Les phosphatases cytosoliques, quant a elles, interviennent plutot dans la transmission du signal en aval de nombreux recepteurs de surface. L'equilibre entre l'activation des proteine-tyrosine phosphatases (PTP) et des proteine-tyrosine kinases (PTK), regle le niveau de phosphorylation des residus tyrosine de nombreuses molecules des reseaux de signalisation intracellulaire. Les PTP contenant des domaines SH2 (SHP-1, SHP-2) s'associent a des proteines phosphorylees sur residu tyrosine et peuvent regler positivement ou negativement la transmission intracellulaire du signal. Elles sont ainsi impliquees dans les mecanismes d'adaptation fine du niveau d'activation cellulaire.

Eric Vivier

Papers

Inhibitory and activatory receptors for MHC class I molecules

Genetic Dissection of the Transducing Subunits of the T‐Cell Antigen Receptor

Erratum and corrigendum: Innate and adaptive immunity: specificities and signaling hierarchies revisited

Structure et fonction du complexe CD16 :ζ :γ des cellules NK

Régulation de l'activité cellulaire par les phosphatases.