Trained innate immunity as underlying mechanism for the long-term, nonspecific effects of vaccines.

NK cells; heterologous immunity; innate immune memory; monocytes/macrophages; vaccination
J Leukoc Biol. 2015 Jul 6. pii: jlb.5RI0315-096R. [Epub ahead of print]
Trained innate immunity as underlying mechanism for the long-term, nonspecific effects of vaccines.
Blok BA, Arts RJ, van Crevel R, Benn CS, Nete MG.

An increasing body of evidence shows that the innate immune system has adaptive characteristics that involve a heterologous memory of past insults. Both experimental models and proof-of-principle clinical trials show that innate immune cells, such as monocytes, macrophages, and NK cells, can provide protection against certain infections in vaccination models independently of lymphocytes. This process is regulated through epigenetic reprogramming of innate immune cells and has been termed "trained immunity." It has been hypothesized that induction of trained immunity is responsible for the protective, nonspecific effects induced by vaccines, such as BCG, measles vaccination, and other whole-microorganism vaccines. In this review, we will present the mechanisms of trained immunity responsible for the long-lasting effects of vaccines on the innate immune system.

Critical role of the NKG2D receptor for NK cell-mediated control and immune escape of B-cell lymphoma.

Endogenous B‐cell lymphoma; NKG2D ligands; NK‐cell activation; Tumor escape; λ‐myc mouse
Eur J Immunol. 2015 Jun 22. doi: 10.1002/eji.201445375. [Epub ahead of print]
Critical role of the NKG2D receptor for NK cell-mediated control and immune escape of B-cell lymphoma.
Belting L, Hömberg N, Przewoznik M, Brenner C, Riedel T, Flatley A, Polić B, Busch DH, Röcken M, Mocikat R.

Little is known on the control of lymphomas by NK cells. Here, we study the role of the NK group 2D (NKG2D) receptor for the immunosurveillance of lymphoma. By using transplantable tumors as well as a λ-myc-transgenic model of endogenously arising lymphoma and NKG2D-deficient mice, we show that NK cells eliminate tumor cells in vivo after receiving two signals. One step involved the activation of NK cells giving rise to IFN-γ expression, which was effected by MHCIlow tumor cells or DCs. However, this was necessary but not sufficient to mediate cytotoxicity. Triggering cytotoxicity additionally required a second step, which could be mediated by engagement of the NKG2D receptor. Thus, NKG2D-deficient NK cells could become activated in vivo, but they were not able to reject transplanted lymphomas or to degranulate in animals bearing autochthonous lymphomas. Tumor growth in NKG2D-deficient λ-myc-transgenic mice was significantly accelerated compared to NKG2D-competent animals. Whereas the latter developed tumors that lost expression of NKG2D ligands (NKG2D-L) in late disease stages, this did not occur in NKG2D-deficient mice. This indicates that NK cells and the NKG2D receptor play a role for control of lymphomas and that selection for NKG2D-L loss mutants provides a mechanism of tumor escape.

The Immune Interplay between Thyroid Papillary Carcinoma and Hepatic Fibrosis.

PLoS One. 2015 Jul 7;10(7):e0132463. doi: 10.1371/journal.pone.0132463. eCollection 2015.
The Immune Interplay between Thyroid Papillary Carcinoma and Hepatic Fibrosis.
Muhanna N, Amer J, Salhab A, Sichel JY, Safadi R.

BACKGROUND:
A high prevalence of thyroid papillary cancer was reported in hepatitis-C-virus (HCV) positive patients. However, the mechanistic role of hepatic-fibrosis in thyroid malignancy progressions is still unclear.
AIM:
We aimed to study the immune-modulatory interactions between thyroid papillary carcinoma and hepatic-fibrosis.
METHODS:
Hepatic-fibrosis was induced in nude-nu-male mice by intra-peritoneal administration of carbon-tetrachloride. To induce thyroid-tumor, a thyroid papillary carcinoma cell line (NPA) was injected subcutaneously in the backs. Fibrotic profile was estimated by α-smooth-muscle-actin (αSMA) expression in liver tissue extracts using western-blots and RT-PCR. Intra-hepatic NK cells were isolated and stained for NK activity (CD107a) by flow cytometry. Liver histopathology (H&E staining), thyroid tumor mass and serum alanine aminotransferase (ALT), serum vascular endothelial growth factor (VEGF) and free-T4 levels were also assessed.
RESULTS:
Ex-vivo: NPA cells were co-cultured with intra-hepatic NK cells isolated from fibrotic mice with/without the tumor were analyzed for CFSE-proliferations. Both tumor groups (with/without hepatic-fibrosis) excreted higher serum free T4 levels. Hepatic-fibrosis increased tumor weight and size and serum free-T4 levels. In addition, tumor induction increased liver injury (both hepatic-fibrosis, necro-inflammation and serum ALT levels). In addition, tumor-bearing animals with hepatic-fibrosis had increased NK activity. NPA tumor-bearing animals increased fibrosis in spite of increased NKactivity; probably due to a direct effect through increased serum free-T4 excretions. Serum VEGF levels were significantly increased in the fibrotic- bearing tumor groups compared to the non-fibrotic groups. In-vitro, NK cells from fibrotic tumor-bearing animals reduced proliferation of NPA cells. This decrease is attributed to increase NK cells activity in the fibrotic animals with the NPA tumors.
CONCLUSIONS:
Our results propose that NK cells although were stimulated in advanced fibrosis with tumor, they lost their anti-tumor and anti-fibrotic activity probably due to secretions of T4 and VEFG and may explain increased risk of thyroid tumors in chronic HCV patients.

Type II NKT Cells in Inflammation, Autoimmunity, Microbial Immunity, and Cancer.

CD1d; autoimmunity; cancer; inflammation; innate immunity; lipids; neutrophils; sulfatide

Front Immunol. 2015 Jun 17;6:316. doi: 10.3389/fimmu.2015.00316. eCollection 2015.
Type II NKT Cells in Inflammation, Autoimmunity, Microbial Immunity, and Cancer.
Marrero I, Ware R, Kumar V.

Natural killer T cells (NKT) recognize self and microbial lipid antigens presented by non-polymorphic CD1d molecules. Two major NKT cell subsets, type I and II, express different types of antigen receptors (TCR) with distinct mode of CD1d/lipid recognition. Though type II NKT cells are less frequent in mice and difficult to study, they are predominant in human. One of the major subsets of type II NKT cells reactive to the self-glycolipid sulfatide is the best characterized and has been shown to induce a dominant immune regulatory mechanism that controls inflammation in autoimmunity and in anti-cancer immunity. Recently, type II NKT cells reactive to other self-glycolipids and phospholipids have been identified suggesting both promiscuous and specific TCR recognition in microbial immunity as well. Since the CD1d pathway is highly conserved, a detailed understanding of the biology and function of type II NKT cells as well as their interplay with type I NKT cells or other innate and adaptive T cells will have major implications for potential novel interventions in inflammatory and autoimmune diseases, microbial immunity, and cancer.

Endogenous ligands of natural killer T cells are alpha-linked glycosylceramides.

Mol Immunol. 2015 Jun 30. pii: S0161-5890(15)00433-2. doi: 10.1016/j.molimm.2015.06.009.
Endogenous ligands of natural killer T cells are alpha-linked glycosylceramides.
Kain L, Costanzo A, Webb B, Holt M, Bendelac A, Savage PB, Teyton L.

The nature of the endogenous ligands for natural killer T (NKT) cells has been debated for more than a decade. Because the mammalian glycosylceramide synthases are invertases, it is believed that in mammals all glycosylceramides are β anomers. However, the possibility that an alternative enzymatic pathway, an unfaithful enzyme, or unique physico-chemical environments could allow the production of small quantities of α anomers should be entertained. Classic biochemical and chemical analysis approaches are not well suited for this challenge as they lack sensitivity. Using a combination of biological assays and new technological approaches, we have unequivocally demonstrated that α glycosylceramides were constitutively produced by mammalian immune cells, loaded onto CD1d and presented to NKT cells both in the thymus and in the periphery. Their amount is controlled tightly by catabolic enzymes, and can be altered in vitro and in vivo to modify NKT cell behavior.

Interleukin 35 (IL-35) and IL-37: Intestinal and peripheral expression by T and B regulatory cells in patients with Inflammatory Bowel Disease.

Cytokine. 2015 Jun 30. pii: S1043-4666(15)00160-X. doi: 10.1016/j.cyto.2015.04.009.
Interleukin 35 (IL-35) and IL-37: Intestinal and peripheral expression by T and B regulatory cells in patients with Inflammatory Bowel Disease.
Fonseca-Camarillo G, Furuzawa-Carballeda J, Yamamoto-Furusho JK.

The aim of the study was to characterize and to quantify peripheral and tissue. IL-35- and IL-37-producing cells in Inflammatory Bowel Disease (IBD) patients. We studied a total of 38 active UC, 31 inactive UC, 17 active CD, and 13 inactive CD and 50 non-inflamed tissues as control group. Gene expression was measured by real time polymerase chain reaction (RT-PCR) and protein expression was evaluated in tissue by immunohistochemistry and in peripheral blood mononuclear cells by flow cytometry. Higher levels of IL-35 was produced by intestinal regulatory B cells and circulating regulatory CD4+ and CD8+ T cells in active vs. inactive disease or healthy donors (P<0.05). The IL-37 was conspicuously synthesized by circulating Bcells, active natural killer cells and monocytes. These results suggest that down-regulation of inflammation in active IBD patients might be based on the increased expression of IL-35 and IL-37.

Inflammation-induced formation of fat-associated lymphoid clusters

Nat Immunol. 2015 Jun 29. doi: 10.1038/ni.3215.
Inflammation-induced formation of fat-associated lymphoid clusters.
Bénézech C, Luu NT, Walker JA, Kruglov AA, Loo Y, Nakamura K, Zhang Y, Nayar S, Jones LH, Flores-Langarica A, McIntosh A, Marshall J, Barone F, Besra G, Miles K, Allen JE, Gray M, Kollias G, Cunningham AF, Withers DR, Toellner KM, Jones ND, Veldhoen M, Nedospasov SA, McKenzie AN, Caamaño JH.

Fat-associated lymphoid clusters (FALCs) are a type of lymphoid tissue associated with visceral fat. Here we found that the distribution of FALCs was heterogeneous, with the pericardium containing large numbers of these clusters. FALCs contributed to the retention of B-1 cells in the peritoneal cavity through high expression of the chemokine CXCL13, and they supported B cell proliferation and germinal center differentiation during peritoneal immunological challenges. FALC formation was induced by inflammation, which triggered the recruitment of myeloid cells that expressed tumor-necrosis factor (TNF) necessary for signaling via the TNF receptors in stromal cells. Natural killer T cells (NKT cells) restricted by the antigen-presenting molecule CD1d were likewise required for the inducible formation of FALCs. Thus, FALCs supported and coordinated the activation of innate B cells and T cells during serosal immune responses.