Shaping of adaptive immunity by innate interactions

In inflamed tissues, the reciprocal interaction between Natural Killer (NK) cells and Dendritic Cells (DC) results in a potent activating cross talk that leads to DC maturation and NK cell activation with acquisition of NK-mediated cytotoxicity against immature DC (iDC). We focused our studies on NK-mediated killing of monocyte-derived iDC and we provided evidence that NK cells that express CD94/NKG2A but not killer Ig-like receptors (KIR) are able to kill autologous iDC. Indeed HLA-E (i.e. the cellular ligand of CD94/NKG2A) is sharply reduced in iDC, whereas it is partially recovered in mDC. The latter are lysed only by a small fraction of NK clones characterized by low levels of CD94/NKG2A expression. Another NK receptor, whose surface density is crucial for the ability to kill iDC, is represented by NKp30, a member of the NCR (Natural Cytotoxicity Receptor) family. We showed that transforming growth factor beta1 (TGFbeta1) treatment results in specific downregulation of NKp30 expression. This effect profoundly inhibits the NK-mediated killing of DC suggesting a possible mechanism by which TGFbeta1-producing DC may acquire resistance to the NK-mediated attack.     

Evasion of innate and adaptive immunity by flaviviruses

After a virus infects an animal, antiviral responses are generated that attempt to prevent dissemination. Interferons, antibody, complement, T and natural killer cells all contribute to the control and eradication of viral infections. Most flaviviruses, with the exception of some of the encephalitic viruses, cause acute disease and do not establish persistent infection. The outcome of flavivirus infection in an animal is determined by a balance between the speed of viral replication and spread, and the immune system response. Although many of the mechanistic details require further elucidation, flaviviruses have evolved specific tactics to evade the innate and adaptive immune response. A more thorough understanding of these principles could lead to improved models for viral pathogenesis and to strategies for the development of novel antiviral agents.     

Bridging innate and adaptive immunity

The Nobel Prize in Physiology or Medicine for 2011 to Jules Hoffmann, Bruce Beutler, and the late Ralph Steinman recognizes accomplishments in understanding and unifying the two strands of immunology, the evolutionarily ancient innate immune response and modern adaptive immunity.     

Phagosome as the organelle linking innate and adaptive immunity

The means by which phagocytosis and antimicrobial defense mechanisms are linked have expanded greatly in recent years. It is now clear that the process of phagocytosis does more than just degrade internalized microbes, but also helps coordinate the actions of the innate and adaptive immune system. This review will discuss the means by which Toll-like receptor signaling pathways are coordinated around the processes of phagocytosis, phagosome trafficking and autophagy and how these signaling pathways influence T-cell-mediated immunity. In this regard, we propose that at the subcellular level, phagosomes represent the smallest definable unit that links innate and adaptive immunity.     

Role of chemokines,innate and adaptive immunity

Polycystic Kidney Disease (PKD) triggers a robust immune system response including changes in both innate and adaptive immunity. These changes involve immune cells (e.g., macrophages and T cells) as well as cytokines and chemokines (e.g., MCP-1) that regulate the production, differentiation, homing, and various functions of these cells. This review is focused on the role of the immune system and its associated factors in the pathogenesis of PKDs as evidenced by data from cell-based systems, animal models, and PKD patients. It also highlights relevant pre-clinical and clinical studies that point to specific immune system components as promising candidates for the development of prognostic biomarkers and therapeutic strategies to improve PKD outcomes.     

Toll-like receptors: linking innate and adaptive immunity

Detection of and response to microbial infections by the immune system depends largely on a family of pattern-recognition receptors called Toll-like receptors (TLRs). These receptors recognize conserved molecular products derived from various classes of pathogens, including Gram-positive and -negative bacteria, DNA and RNA viruses, fungi and protozoa. Recognition of ligands by TLRs leads to a series of signaling events resulting in induction of acute responses necessary to kill the pathogen. TLRs are also responsible for the induction of dendritic cell maturation, which is responsible and necessary for initiation of adaptive immune responses. Although TLRs control induction of adaptive immunity, it is not clear at this point how responses are appropriately tailored by individual TLRs to the advantage of the host.     

Monocyte-derived dendritic cells in innate and adaptive immunity

Monocytes have been classically considered essential elements in relation with innate immune responses against pathogens, and inflammatory processes caused by external aggressions, infection and autoimmune disease. However, although their potential to differentiate into dendritic cells (DCs) was discovered 14 years ago, their functional relevance with regard to adaptive immune responses has only been uncovered very recently. Studies performed over the last years have revealed that monocyte-derived DCs play an important role in innate and adaptive immunity, due to their microbicidal potential, capacity to stimulate CD4(+) and CD8(+) T-cell responses and ability to regulate Immunoglobulin production by B cells. In addition, monocyte-derived DCs not only constitute a subset of DCs formed at inflammatory foci, as previously thought, but also comprise different subsets of DCs located in antigen capture areas, such as the skin and the intestinal, respiratory and reproductive tracts.     

Control of mucosal polymicrobial populations by innate immunity

The gastrointestinal tract carries out the complex process of localizing the polymicrobial populations of the indigenous microbiota to the lumenal side of the GI mucosa while absorbing nutrients from the lumen and preventing damage to the mucosa. This process is accomplished through a combination of physical, innate and adaptive host defences and a 'strategic alliance' with members of the microbiota. To cope with the constant exposure to a diverse microbial community, the GI tract, through the actions of a number of specialized cells in the epithelium and lamina propria, has layers of humoral, physical and cellular defences that limit attachment, invasion and dissemination of the indigenous microbiota. However, the role of the microbiota in this dynamic balance is vital and serves as another level of 'innate' defence. We are just beginning to understand how bacterial metabolites aid in the control of potential pathogens within the microbiota and limit inflammatory responses to the microbiota, concepts that will impact our understanding of the biological effects of antibiotics, diet and probiotics on mucosal inflammatory responses.     

Unveiling the roles of autophagy in innate and adaptive immunity

Cells digest portions of their interiors in a process known as autophagy to recycle nutrients, remodel and dispose of unwanted cytoplasmic constituents. This ancient pathway, conserved from yeast to humans, is now emerging as a central player in the immunological control of bacterial, parasitic and viral infections. The process of autophagy may degrade intracellular pathogens, deliver endogenous antigens to MHC-class-II-loading compartments, direct viral nucleic acids to Toll-like receptors and regulate T-cell homeostasis. This Review describes the mechanisms of autophagy and highlights recent advances relevant to the role of autophagy in innate and adaptive immunity.     

Roles of heat-shock proteins in innate and adaptive immunity

Heat-shock proteins (HSPs) are the most abundant and ubiquitous soluble intracellular proteins. In single-cell organisms, invertebrates and vertebrates, they perform a multitude of housekeeping functions that are essential for cellular survival. In higher vertebrates, their ability to interact with a wide range of proteins and peptides--a property that is shared by major histocompatibility complex molecules--has made the HSPs uniquely suited to an important role in organismal survival by their participation in innate and adaptive immune responses. The immunological properties of HSPs enable them to be used in new immunotherapies of cancers and infections.     

Dendritic cell-induced activation of adaptive and innate antitumor immunity

While studying Ag-pulsed syngeneic dendritic cell (DC) immunization, we discovered that surprisingly, unpulsed DCs induced protection against tumor lung metastases resulting from i.v. injection of a syngeneic BALB/c colon carcinoma CT26 or a syngeneic C57BL/6 lung carcinoma LL/2. Splenocytes or immature splenic DCs did not protect. The protection was mediated by NK cells, in that it was abrogated by treatment with anti-asialo-GM1 but not anti-CD8, and was induced by CD1(-/-) DCs unable to stimulate NKT cells, but did not occur in beige mice lacking NK cells. Protection correlated with increased NK activity, and increased infiltration of NK but not CD8(+) cells in lungs of tumor-bearing mice. Protection depended on the presence of costimulatory molecules CD80, CD86, and CD40 on the DCs, but surprisingly did not require DCs that could make IL-12 or IL-15. Unexpectedly, protection sensitive to anti-asialo-GM1 and increased NK activity were still present 14 mo after DC injection. As NK cells lack memory, we found by depletion that CD4(+) not CD8(+) T cells were required for induction of the NK antitumor response. The role of DCs and CD4(+) T cells provides a novel mechanism for NK cell induction and innate immunity against cancer that may have potential in preventing clinical metastases.     

NK cells at the interface between innate and adaptive immunity

In recent years a novel concept has emerged indicating that the actual role of natural killer (NK) cells is not confined to the destruction of virus-infected cells or tumors. Indeed, different NK subsets exist that display major functional differences in their cytolytic activity, cytokine production and homing capabilities. In particular, CD56(high) CD16(-) NK cells that largely predominate in lymph nodes, have little cytolytic activity but release high levels of cytokines whereas CD56(low) CD16(+) NK cells that predominate in peripheral blood and inflamed tissues, display lower cytokine production, but potent cytotoxicity. The latter is characterized by granule polarization and exocytosis of various proteins including perforin and granzymes that mediate target cell killing. The recruitment of CD56(low) CD16(+) NK cells into inflamed peripheral tissues is orchestrated by various chemochines including the newly identified Chemerin. At these sites, NK cells, upon engagement of different triggering receptors become activated and upregulate their cytokine production and cytotoxicity after interaction with myeloid dendritic cells (DCs). Importantly, during this interaction NK cells also mediate the 'editing' of DCs undergoing maturation. This process appears to play a crucial role in shaping both innate and adaptive immune responses. Indeed, only DCs undergoing this NK-mediated quality control would become fully mature and capable of inducing priming of protective Th1 responses.     

Regulation of innate and adaptive immunity by the female sex hormones oestradiol and progesterone

Women mount more vigorous antibody- and cell-mediated immune responses following either infection or vaccination than men. The incidence of most autoimmune diseases is also higher in women than in men; however, during pregnancy many autoimmune diseases go into remission, only to flare again in the early post-partum period. Successful pregnancy requires that the female immune system tolerate the presence of a semi-allogeneic graft for 9 months. Oral contraceptive use can increase susceptibility to certain genital tract infections and sexually transmitted diseases in women. Moreover, treatment of mice and rats with female sex hormones is required to establish animal models of genital tract Chlamydia, Neisseria and Mycoplasma infection. This review describes what is currently known about the effects of the female sex hormones oestradiol and progesterone on innate and adaptive immune responses in order to provide a framework for understanding these sex differences. Data from both human and animal studies will be reviewed.     

Interleukin-12 and the regulation of innate resistance and adaptive immunity

Interleukin-12 (IL-12) is a heterodimeric pro-inflammatory cytokine that induces the production of interferon-gamma (IFN-gamma), favours the differentiation of T helper 1 (T(H)1) cells and forms a link between innate resistance and adaptive immunity. Dendritic cells (DCs) and phagocytes produce IL-12 in response to pathogens during infection. Production of IL-12 is dependent on differential mechanisms of regulation of expression of the genes encoding IL-12, patterns of Toll-like receptor (TLR) expression and cross-regulation between the different DC subsets, involving cytokines such as IL-10 and type I IFN. Recent data, however, argue against an absolute requirement for IL-12 for T(H)1 responses. Our understanding of the relative roles of IL-12 and other factors in T(H)1-type maturation of both CD4+ and CD8+ T cells is discussed here, including the participation in this process of IL-23 and IL-27, two recently discovered members of the new family of heterodimeric cytokines.     

Neutrophils in the activation and regulation of innate and adaptive immunity

Neutrophils have long been viewed as the final effector cells of an acute inflammatory response, with a primary role in the clearance of extracellular pathogens. However, more recent evidence has extended the functions of these cells. The newly discovered repertoire of effector molecules in the neutrophil armamentarium includes a broad array of cytokines, extracellular traps and effector molecules of the humoral arm of the innate immune system. In addition, neutrophils are involved in the activation, regulation and effector functions of innate and adaptive immune cells. Accordingly, neutrophils have a crucial role in the pathogenesis of a broad range of diseases, including infections caused by intracellular pathogens, autoimmunity, chronic inflammation and cancer.