Regulation of the innate immune cells during pregnancy: An immune checkpoint perspective

The foetus can be regarded as a half-allograft implanted into the maternal body. In a successful pregnancy, the mother does not reject the foetus because of the immune tolerance mechanism at the maternal-foetal interface. The innate immune cells are a large part of the decidual leukocytes contributing significantly to a successful pregnancy. Although the contributions have been recognized, their role in human pregnancy has not been completely elucidated. Additionally, the accumulated evidence demonstrates that the immune checkpoint molecules expressed on the immune cells are co-inhibitory receptors regulating their activation and biological function. Therefore, it is critical to understand the immune microenvironment and explore the function of the innate immune cells during pregnancy. This review summarizes the classic immune checkpoints such as PD-1, CTLA-4 and some novel molecules recently identified, including TIM-3, CD200, TIGIT and the Siglecs family on the decidual and peripheral innate immune cells during pregnancy. Furthermore, it emphasizes the role of the immune checkpoint molecules in pregnancy-associated complications and reproductive immunotherapy.     

Conceptus-modulated innate immune function during early pregnancy in ruminants: a review

This review focuses on the innate immune events modulated by conceptus signaling during early pregnancy in ruminants. Interferon-tau (IFN-τ) plays a role in the recognition of pregnancy in ruminants, which involves more than the inhibition of luteolytic pulses of PGF2α to maintain corpus luteum function. For successful pregnancy establishment, the allogenic conceptus needs to prevent rejection by the female. Therefore, IFN-τ exerts paracrine and endocrine actions to regulate the innate immune system and prevent conceptus rejection. Additionally, other immune regulators work in parallel with IFN-τ, such as the pattern recognition receptors (PRR). These receptors are activated during viral and bacterial infections and in early pregnancy, but it remains unknown whether PPR expression and function are controlled by IFN-τ. Therefore, this review focuses on the main components of the innate immune response that are involved with early pregnancy and their importance to avoid conceptus rejection.     

The innate immune system in the intestine

The innate immune system provides the first line of host defense against invading pathogens. Innate immune responses are initiated by germline-encoded PRR, which recognize specific structures expressed by microorganisms. TLR are a family of PRR which sense a wide range of microorganisms, including bacteria, fungi, protozoa and viruses. TLR are also expressed in the intestine and are critical for intestinal homeostasis. Recently, cytoplasmic PRR, such as NLR and RLR, have been shown to detect pathogens that have invaded the cytosol. One of the NLR, NOD2, is thought to be involved in the pathogenesis of Crohn's disease. This review focuses on the innate immune responses triggered by PRR in the intestine.     

The macrophage-inducible C-type lectin, mincle, is an essential component of the innate immune response to Candida albicans

The recognition of carbohydrate moieties by cells of the innate immune system is emerging as an essential element in antifungal immunity, but despite the number and diversity of lectins expressed by innate immune cells, few carbohydrate receptors have been characterized. Mincle, a C-type lectin, is expressed predominantly on macrophages, and is here shown to play a role in macrophage responses to the yeast Candida albicans. After exposure to the yeast in vitro, Mincle localized to the phagocytic cup, but it was not essential for phagocytosis. In the absence of Mincle, production of TNF-alpha by macrophages was reduced, both in vivo and in vitro. In addition, mice lacking Mincle showed a significantly increased susceptibility to systemic candidiasis. Thus, Mincle plays a novel and nonredundant role in the induction of inflammatory signaling in response to C. albicans infection.     

The role of scavenger receptors in the innate immune system

Akey aspect of the innate immune system is the ability to discriminate between self and infectious nonself. This is achieved through pattern recognition receptors which directly recognise molecular epitopes expressed by microbes. Scavenger receptors (SRs) have been studied primarily due to their ability to bind and internalise modified lipoproteins, suggesting an important role in foam cell formation and the pathogenesis of atherosclerosis. However, the ability of some SRs to function as pattern recognition receptors through their binding of a wide variety of pathogens indicates a potential role in host defence. This review will detail our current understanding of the function of SRs in innate immunity, and in the initiation of aquired immune responses.     

Brucella abortus DNA is a major bacterial agonist to activate the host innate immune system

Immunity against Brucella abortus depends on the recognition of pathogen-associated molecular patterns (PAMPs) by pattern recognition receptors (PRRs). Signaling pathways triggered by Brucella DNA involves TLR9, AIM2 and possibly STING and MAVS. Herein, we review the advances in B. abortus DNA sensing by host innate immune receptors and the progress in this field.     

The role of dendritic cells in the innate immune system

Dendritic cells (DCs) are bone-marrow-derived leucocytes that are specialised antigen-presenting cells capable of stimulating a primary T-lymphocyte response to specific antigen. In this chapter we discuss the role DCs play in the innate response acting as a critical link with the adaptive response and the influence of the innate response on dendritic cells.     

The spider acylpolyamine Mygalin is a potent modulator of innate immune responses

Mygalin is an antibacterial molecule isolated from the hemocytes of the spider Acanthoscurria gomesiana. It was identified as bis-acylpolyamine spermidine. We evaluated the modulator effects of synthetic Mygalin in the innate immune response. We demonstrate that Mygalin induces IFN-γ synthesis by splenocytes increasing the nitrite secretion by splenocytes and macrophages. A specific inhibitor of iNOS abrogated Mygalin-induced nitrite production in macrophages independent of IFN-γ activation. In addition, Mygalin-activated macrophages produced TNF-α but not IL-1β, demonstrating that Mygalin does not act directly on the inflammasome. Furthermore, this compound did not affect spontaneous or Concanavalin A-induced proliferative responses by murine splenocytes and did not induce IL-5 or apoptosis of splenocytes or bone marrow-derived macrophages. These data provide evidence that Mygalin modulates the innate immune response by inducing IFN-γ and NO synthesis. The combined immune regulatory and antibacterial qualities of Mygalin should be explored as a strategy to enhance immune responses in infection.     

Immunological memory within the innate immune system

Immune memory has traditionally been the domain of the adaptive immune system, present only in antigen‐specific T and B cells. The purpose of this review is to summarize the evidence for immunological memory in lower organisms (which are not thought to possess adaptive immunity) and within specific cell subsets of the innate immune system. A special focus will be given to recent findings in both mouse and humans for specificity and memory in natural killer (NK) cells, which have resided under the umbrella of innate immunity for decades. The surprising longevity and enhanced responses of previously primed NK cells will be discussed in the context of several immunization settings.     

Activation of innate immune responses in the central nervous system during reovirus myelitis

Reovirus infection of the murine spinal cord (SC) was used as a model system to investigate innate immune responses during viral myelitis, including the activation of glia (microglia and astrocytes) and interferon (IFN) signaling and increased expression of inflammatory mediators. Reovirus myelitis was associated with the pronounced activation of SC glia, as evidenced by characteristic changes in cellular morphology and increased expression of astrocyte and microglia-specific proteins. Expression of inflammatory mediators known to be released by activated glia, including interleukin-1β (IL-1β), tumor necrosis factor alpha (TNF-α), chemokine (C-C motif) ligand 5 (CCL 5), chemokine (C-X-C motif) ligand 10 (CXCL10), and gamma interferon (IFN-γ), was also significantly upregulated in the SC of reovirus-infected animals compared to mock-infected controls. Reovirus infection of the mouse SC was also associated with increased expression of genes involved in IFN signaling, including IFN-stimulated genes (ISG). Further, reovirus infection of mice deficient in the expression of the IFN-α/β receptor (IFNAR(-/-)) resulted in accelerated mortality, demonstrating that IFN signaling is protective during reovirus myelitis. Experiments performed in ex vivo SC slice cultures (SCSC) confirmed that resident SC cells contribute to the production of at least some of these inflammatory mediators and ISG during reovirus infection. Microglia, but not astrocytes, were still activated, and glia-associated inflammatory mediators were still produced in reovirus-infected INFAR(-/-) mice, demonstrating that IFN signaling is not absolutely required for these neuroinflammatory responses. Our results suggest that activated glia and inflammatory mediators contribute to a local microenvironment that is deleterious to neuronal survival.     

Peptidoglycan recognition proteins of the innate immune system

Peptidoglycan (PGN) is the major component of bacterial cell walls and one of the main microbial products recognized by the innate immune system. PGN recognition is mediated by several families of pattern recognition molecules, including Toll-like receptors, nucleotide-binding oligomerization domain-containing proteins, and peptidoglycan recognition proteins (PGRPs). However, only the interaction of PGN with PGRPs, which are highly conserved from insects to mammals, has so far been characterized at the molecular level. Here, we describe recent structural studies of PGRPs that reveal the basis for PGN recognition and provide insights into the signal transduction and antibacterial activities of these innate immune proteins.     

Recognition of herpesviruses by the innate immune system

Advances in innate immunity over the past decade have revealed distinct classes of pattern recognition receptors (PRRs) that detect pathogens at the cell surface and in intracellular compartments. This has shed light on how herpesviruses, which are large disease-causing DNA viruses that replicate in the nucleus, are initially recognized during cellular infection. Surprisingly, this involves multiple PRRs both on the cell surface and within endosomes and the cytosol. In this article we describe recent advances in our understanding of innate detection of herpesviruses, how this innate detection translates into anti-herpesvirus host defence, and how the viruses seek to evade this innate detection to establish persistent infections.     

CCR4 is a key modulator of innate immune responses

CCR4 is recognized as a key receptor in Th2-associated immune processes, although very little is known about its role in innate immunity. Previous studies reported increased resistance to LPS-induced lethality in CCR4(-/-) mice compared with wild-type mice. This study demonstrates that CCR4(-/-) mice are similarly resistant to challenge with other TLR agonists, as well as bacterial peritonitis. Resistance was associated with enhanced early leukocyte recruitment, increased TLR expression, a skewed type 2 cytokine/chemokine profile, and improved bacterial clearance. Macrophages from CCR4(-/-) mice exhibited many features consistent with alternative activation, including elevated secretion of type 2 cytokines/chemokines and the found in inflammatory zone 1 (FIZZ1) protein. MyD88-dependent NF-kappaB signaling was significantly down-regulated in CCR4(-/-) macrophages, whereas p38 MAPK and JNK activation were conversely increased. These data stress the importance of CCR4 in macrophage differentiation and innate immune responses to pathogens, as well as the involvement of chemokine receptor expression in TLR signaling regulation.     

Control of host inflammatory responsiveness by indigenous microbiota reveals an adaptive component of the innate immune system

We are not alone. The indigenous microbiota colonizes exposed surfaces and aids their hosts in several physiological activities. The transition between a non-colonized to a colonized state is associated with modification on the pattern of host inflammatory responsiveness. Therefore, innate immunity adapts to the colonized state of the host, suggesting that there is an acquired component in innate immune responses.