Although gammadelta T cells express clonally distributed T-cell receptors (TCRs), a hallmark of adaptive immunity, they are classically considered as innate-like effectors, owing to the high frequency of preactivated gammadelta T cells, with restricted antigen recognition repertoire in particular tissue locations. Actually, such features are shared only by a fraction of gammadelta T-cell subsets located in the skin and reproductive organ mucosa in rodents or in peripheral blood in humans. By contrast, other gammadelta subsets, e.g. those found in rodent and human spleen, show diverse antigenic reactivity patterns and mixed naive/memory phenotypes. Thus, gammadelta T cells are made of both 'primitive' subsets endowed with innate-like properties and 'evolved' subsets able to mount anamnestic responses like conventional major histocompatibility complex-restricted alphabeta T cells. In this article, we show that human gammadelta T cells, although heterogeneous, do share recurrent innate features that distinguish them from mainstream alphabeta T cells. In particular, most of them are activated on TCR- or natural killer receptor-mediated recognition of a restricted set of conserved yet poorly defined endogenous stress determinants. This rather simple recognition mechanism allows human gammadelta T cells to discriminate healthy cells from altered cells and to exert a variety of immunostimulatory or regulatory functions. The recent availability of synthetic gammadelta T-cell agonists mimicking these natural stress-induced ligands have fostered development of immunotherapeutic strategies, with broad indications against infectious and tumor diseases, which are briefly reviewed here.

SUMMARY To elucidate how the proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitor alirocumab modulates lipoprotein(a) [Lp(a)] plasma levels, the authors performed a series of Lp(a) uptake studies in primary human hepatocytes and dermal fibroblasts and measured Lp(a) secretion from human hepatocytes. They found that Lp(a) cellular uptake occurred in a low-density lipoprotein receptor–independent manner. Neither PCSK9 nor alirocumab altered Lp(a) internalization. By contrast, the secretion of apolipoprotein (a) from human hepatocytes was sharply increased by PCSK9, an effect that was reversed by alirocumab. They propose that PCSK9 does not significantly modulate Lp(a) catabolism, but rather enhances the secretion of Lp(a) from liver cells.

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Epithelial ovarian cancer (EOC) is a significant cause of cancer-related mortality in women, and there has been no substantial decrease in the death rates due to EOC in the last three decades. Thus, basic knowledge regarding ovarian tumor cell biology is urgently needed to allow the development of innovative treatments for EOC. Traditionally, EOC has not been considered an immunogenic tumor, but there is evidence of an immune response to EOC in patients. Clinical data demonstrate that an antitumor immune response and immune evasion mechanisms are correlated with a better and lower survival, respectively, providing evidence for the immunoediting hypothesis in EOC. This review focuses on the immune response and immune suppression in EOC. The immunological roles of chemotherapy and surgery in EOC are also described. Finally, we detail pilot data supporting the efficiency of immunotherapy in the treatment of EOC and the emerging concept that immunomodulation aimed at counteracting the immunosuppressive microenvironment must be associated with immunotherapy strategies.

IntroductionOn recognition of antigenic peptides bound to major histocompatibility complex (MHC) molecules, the T cell receptor (TCR) complex generates essential biochemical signals for T-cell activation. 1 Sensitivity of T cells to TCR-dependent activation is greatly enhanced when CD4 or CD8 proteins are engaged at the same time. 2 These proteins have been referred to as coreceptors, 3 because they are supposed to bind the same MHC molecule engaged by the TCR, and are supposed to drag the associated tyrosine kinase Lck in contact with the TCR-associated CD3 zeta chains to initiate the phosphorylation events leading to T-cell activation. 4 While CD8 binds MHC class I molecules, the CD4 coreceptor binds MHC class II molecules, and augments signaling via the TCR by up to 100-fold. 2 Structure-function studies and crystallographic analysis of CD4-MHC class II complexes indicate that CD4 interacts with its residues on the D1 domain with both ␣2 and ␤2 domains of the MHC class II ␣␤ heterodimer. [5][6][7][8][9] Invariant natural killer T cells (iNKT) cells are a subset of nonconventional T lymphocytes present in most mammalian species studied so far that share several phenotypic features with natural killer cells, such as surface expression of CD161. 10 Human iNKT cells express an invariant V␣24-J␣Q TCR␣ chain paired preferentially with junctionally diverse V␤11D␤J␤ regions. 11,12 This semi-invariant TCR (invTCR) is strikingly conserved in evolution, and recognizes lipids and glycolipids presented by CD1d, a member of the CD1 family of antigen-presenting molecules exhibiting an MHC-class I-like structure. [13][14][15] The invTCR display an exquisite specificity for the xenogeneic glycosphingolipid ␣-GalCer, presented by CD1d, which can be used to selectively activate iNKT cells in vitro and in vivo. 16,17 A number of more physiologic CD1d-restricted antigens recognized by iNKT cells have been recently identified. [18][19][20][21][22][23][24] These include bacterial glycolipids, endogenous glycolipids, tumor-derived glycoplipids, and phospholipids, as well as nonlipidic molecules. iNKT cells can be found in various peripheral organs including spleen, lymph nodes, and liver. Peripheral iNKT cells display a memory activated phenotype and can rapidly secrete large amounts of cytokines including IFN-␥, TNF-␣, IL-4, and IL-13 on antigenic activation. Production of cytokines by activated iNKT cells can play a critical role in the pathogenesis of various infectious, autoimmune, and allergic diseases, as well as in the control of tumor progression 25 (see this reference for a recent review).Mature iNKT cells are either CD4 ϩ , CD8␣␣ ϩ , or CD4 Ϫ CD8 Ϫ double negative (DN). 10 The very low frequency of CD8␣␤ ϩ cells among mature iNKT cells has been related to the early deletion of CD8 ϩ iNKT cells during thymic development, 12,26 presumably caused by high-avidity interactions between TCR/CD8 and self-CD1. Although direct interaction between CD8 and CD1d has not been formally demonstrated, these data suggest that CD8 functions ...

Residual LDLR expression in HoFH is a major determinant of LDL-C levels and seems to drive their individual response to evolocumab.

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Total word count (including tables and figure legends): 3927 Number of tables and figures : 4 ABSTRACT (Word count 250) Background and aims -PCSK9 is an endogenous inhibitor of LDL receptor pathway.Recently, Mendelian randomization studies have raised a doubt about the diabetogenic risk of PCSK9 inhibitors. Here, we assessed the relationship between plasma PCSK9 levels and the risk of new onset diabetes (NOD).Methods -Fasting plasma PCSK9 levels were measured at baseline by ELISA in subjects without lipid lowering treatment in IT-DIAB (n=233 patients with prediabetes, follow-up 5 years) and ELSA-Brasil (n=1,751; 27.5% with prediabetes, follow-up 4 years) prospective cohorts. The primary outcome in both studies was the incidence of NOD. The association of NOD with plasma PCSK9 levels was studied using multivariate Cox models. Results -Plasma PCSK9 levels were not significantly associated with NOD in IT-DIAB (HR (+1SD) 0.96, CI95% [0.76; 1.21]) and ELSA-Brasil (OR (+1SD) 1.13 [0.89; 1.42]). In ELSA-Brasil, a significant positive association between PCSK9 and worsening of glucose homeostasis, including the progression from normoglycemia to prediabetes, was found (OR (+1SD) 1.17 [1.04; 1.30], P=0.0074). Plasma PCSK9 concentration was also positively associated with the change in fasting plasma glucose between the first and second visit in ELSA-Brasil (β = 0.053, CI95% [0.006; 0.10], P=0.026). Plasma PCSK9 levels positively correlated with total cholesterol in IT-DIAB and ELSA-Brasil, but not with glucose homeostasis parameters, except for a positive correlation with HOMA-IR in ELSA-Brasil.Conclusions -Plasma PCSK9 levels were not significantly associated with NOD risk in longitudinal analyses. These data suggest that inhibition of the PCSK9 extra-cellular pathway should not be deleterious for glucose homeostasis.