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The barriers presented by immune suppression in the ovarian tumor microenvironment present one of the biggest challenges to development of successful tumor vaccine strategies for prevention of disease recurrence and progression following primary surgery and chemotherapy. New insights gained over the last decade have revealed multiple mechanisms of immune regulation, with ovarian tumor-associated macrophages/DC likely to fulfill a central role in creating a highly immunosuppressive milieu that supports disease progression and blocks anti-tumor immunity. This review provides an appraisal of some of the key signaling pathways that may contribute to immune suppression in ovarian cancer, with a particular focus on the potential involvement of the c-KIT/PI3K/AKT, wnt/β-catenin, IL-6/STAT3 and AhR signaling pathways in regulation of indoleamine 2,3-dioxygenase expression in tumor-associated macrophages. Knowledge of intercellular and intracellular circuits that shape immune suppression may afford insights for development of adjuvant treatments that alleviate immunosuppression in the tumor microenvironment and enhance the clinical efficacy of ovarian tumor vaccines.

Toll-like receptors (TLRs) are important for recognizing a variety of pathogens, including protozoan parasites, and initiating innate immune responses against them. TLRs are localized on the cell surface as well as in the endosome, and are implicated in innate sensing of these parasites. In this review, we will discuss recent findings on the identification of parasite-derived pathogen associated molecular patterns and the TLRs that bind them. The role of these TLRs in initiating the immune response against protozoan parasitic infections in vivo will be presented in the context of murine models of infection utilizing TLR-deficient mice. Additionally, we will explore evidence that TLRs and genetic variants of TLRs may impact the outcome of these parasitic infections in humans.

Leishmania donovani (LD), the causative agent of visceral leishmaniasis (VL), extracts membrane cholesterol from macrophages and disrupts lipid rafts, leading to their inability to stimulate T cells. Restoration of membrane cholesterol by liposomal delivery corrects the above defects and offers protection in infected hamsters. To reinforce further the protective role of cholesterol in VL, mice were either provided a high-cholesterol (atherogenic) diet or underwent statin treatment. Subsequent LD infection showed that an atherogenic diet is associated with protection, whereas hypocholesterolemia due to statin treatment confers susceptibility to the infection. This observation was validated in apolipoprotein E knockout mice (AE) mice that displayed intrinsic hypercholesterolemia with hepatic granuloma, production of host-protective cytokines, and expansion of antileishmanial CD8(+)IFN- γ (+) and CD8(+)IFN- γ (+)TNF- α (+) T cells in contrast to the wild-type C57BL/6 (BL/6) mice when infected with LD. Normal macrophages from AE mice (N-AE-MΦ) showed 3-fold higher membrane cholesterol coupled with increased fluorescence anisotropy (FA) compared with wild-type macrophage (N-BL/6-MΦ). Characterization of in vitro LD-infected AE macrophage (LD-AE-MΦ) revealed intact raft architecture and ability to stimulate T cells, which were compromised in LD-BL/6-MΦ. This study clearly indicates that hypercholesterolemia, induced intrinsically or extrinsically, can control the pathogenesis of VL by modulating immune repertoire in favor of the host.

Blood-stage Plasmodium chabaudi chabaudi AS infection requires cell- and Ab-mediated immunity to control acute and persistent infection, respectively. ICOS regulates CD4+ T cell activation and promotes the induction of follicular Th (TFH) cells, CD4+ T cells that support B cell affinity maturation within germinal centers (GCs), resulting in the production of high-affinity Abs. In this article, we demonstrate that, in response to P. c. chabaudi AS infection, the absence of ICOS resulted in an enhanced Th1 immune response that reduced peak parasitemia. Despite the absence of ICOS, CD4+ T cells were capable of expressing PD-1, B cell lymphoma 6, and CXCR5 during early infection, indicating TFH development was not impaired. However, by day 21 postinfection, Icos−/− mice accumulated fewer splenic TFHs compared with Icos+/+ mice, leading to substantially fewer GC B cells and a decrease in affinity, but not production, of parasite-specific isotype-switched Abs. Moreover, treatment of mice with anti–ICOS ligand Abs to modulate ICOS–ICOS ligand signaling revealed a requirement for ICOS in TFH differentiation only after day 6 postinfection. Ultimately, the quality and quantity of isotype-switched Abs produced in Icos−/− mice declined over time, resulting in impaired control of persistent parasitemia. Collectively, these data suggest ICOS is not required for TFH induction during P. c. chabaudi AS infection or production of isotype-switched Abs, but it is necessary for maintenance of a sustained high-affinity, protective Ab response.

Infections due to protozoa of the genus Leishmania are a major worldwide health problem, with high endemicity in developing countries. The aim of this study was to evaluate the in vitro antileishmanial activity of the acetone and methanol leaf extracts of Anisomeles malabarica , flower of Gloriosa superba , leaf of Ocimum basilicum , leaf and seed of Ricinus communis against promastigotes form of Leishmania donovani . Antiparasitic evaluations of different plant crude extracts were performed on 96 well plates at 37 °C for 24–48 h. Out of the 10 experimental plant extracts tested, the leaf methanol extracts of A . malabarica , and R . communis showed good antileishmanial activity (IC 50 = 126 ± 19.70 and 184 ± 39.33 μg/mL), respectively against promastigotes. Effective antileishmanial activity was observed making these plants as good candidates for isolation of antiprotozoal compounds which could serve as new lead structures for drug development.

B-1 cells are known for their innate, polyreactive BCR repertoire, and proficiency at polarizing T cells towards inflammatory effector T cells, a critical component in host defense and autoimmunity. B-1 cells are antigen presenting cells (APCs) and express MHCII proteins to bind and display self and foreign peptides to CD4 T cells. H2-M edits peptide-MHCII complexes to ensure display of stably bound peptides by APCs. Absence of H2-M has most widely been studied for its impact on T cell activation, but knowledge of how this protein affects the development and function of APCs is lacking. We found that absence of H2-M down-regulated the surface expression and altered the distribution of MHCII molecules in B cells across lymphoid organs. Importantly, in H2-M KO mice, compared to the wild-type C57BL/6 (B6) mice, the frequency and abundance of B-1 cells, but not conventional B-2 cells was affected. Interestingly, the H2-M mediated effect on B-1 cell population was only evident in I-Ab expressing B6, not in Balb/c (I-Ad/I-Ed), indicating an MHCII haplotype dependent effect. Decrease in B-1 cell number was evident in both immature and mature B-1 cells, further indicating an H2-M mediated developmental defect of B-1 cells. In H2-M KO mice, B-1 cells display a significantly lower self-renewal capacity and higher rate of apoptosis compared to WT B6. Despite a lower total B-1 cell number, the frequency of B-1 cells specific for predominant self-antigens (like – phosphatidylcholine) is increased in H2-M KO mice, indicating skewing of B-1 BCR repertoire in absence of H2-M. Collectively, these data identify a novel impact of H2-M/MHCII interaction that regulates the development of B-1 cells and influences the selection of mature B-1 cell clones in the periphery.