More than any other cytokine family, the interleukin (IL)-1 family is closely linked to the innate immune response. This linkage became evident upon the discovery that the cytoplasmic domain of the IL-1 receptor type I is highly homologous to the cytoplasmic domains of all Toll-like receptors (TLRs). Thus, fundamental inflammatory responses such as the induction of cyclooxygenase type 2, increased expression of adhesion molecules, or synthesis of nitric oxide are indistinguishable responses of both IL-1 and TLR ligands. Both families nonspecifically affect antigen recognition and lymphocyte function. IL-1β is the most studied member of the IL-1 family because of its role in mediating autoinflammatory diseases. Although the TLR and IL-1 families evolved to assist in host defense against infection, unlike the TLR family, the IL-1 family also includes members that suppress inflammation, both specifically within the IL-1 family but also nonspecifically for TLR ligands and the innate immune response.

Immunological and Inflammatory Functions of the Interleukin-1 Family

Natural killer (NK) cells are populations of lymphocytes that can be activated to mediate significant levels of cytotoxic activity and produce high levels of certain cytokines and chemokines. NK cells respond to and are important in defense against a number of different infectious agents. The first indications for this function came from the observations that virus-induced interferons alpha/beta (IFN-alpha and -beta) are potent inducers of NK cell-mediated cytotoxicity, and that NK cells are important contributors to innate defense against viral infections. In addition to IFN-alpha/beta, a wide range of other innate cytokines can mediate biological functions regulating the NK cell responses of cytotoxicity, proliferation, and gamma interferon (IFN-gamma) production. Certain, but not all, viral infections induce interleukin 12 (IL-12) to elicit NK cell IFN-gamma production and antiviral mechanisms. However, high levels of IFN-alpha/beta appear to be unique and/or uniquely dominant in the context of viral infections and act to regulate other innate responses, including induction of NK cell proliferation in vivo and overall negative regulation of IL-12 production. A detailed picture is developing of particular innate cytokines activating NK cell responses and their consorted effects in providing unique endogenous milieus promoting downstream adaptive responses, most beneficial in defense against viral infections.

NATURAL KILLER CELLS IN ANTIVIRAL DEFENSE: Function and Regulation by Innate Cytokines

There have been no major advances for the treatment of metastatic urothelial bladder cancer (UBC) in the last 30 years. Chemotherapy is still the standard of care. Patient outcomes, especially for those in whom chemotherapy is not effective or is poorly tolerated, remain poor. One hallmark of UBC is the presence of high rates of somatic mutations. These alterations may enhance the ability of the host immune system to recognize tumour cells as foreign owing to an increased number of antigens. However, these cancers may also elude immune surveillance and eradication through the expression of programmed death-ligand 1 (PD-L1; also called CD274 or B7-H1) in the tumour microenvironment. Therefore, we examined the anti-PD-L1 antibody MPDL3280A, a systemic cancer immunotherapy, for the treatment of metastatic UBC. MPDL3280A is a high-affinity engineered human anti-PD-L1 monoclonal immunoglobulin-G1 antibody that inhibits the interaction of PD-L1 with PD-1 (PDCD1) and B7.1 (CD80). Because PD-L1 is expressed on activated T cells, MPDL3280A was engineered with a modification in the Fc domain that eliminates antibody-dependent cellular cytotoxicity at clinically relevant doses to prevent the depletion of T cells expressing PD-L1. Here we show that MPDL3280A has noteworthy activity in metastatic UBC. Responses were often rapid, with many occurring at the time of the first response assessment (6 weeks) and nearly all were ongoing at the data cutoff. This phase I expansion study, with an adaptive design that allowed for biomarker-positive enriched cohorts, demonstrated that tumours expressing PD-L1-positive tumour-infiltrating immune cells had particularly high response rates. Moreover, owing to the favourable toxicity profile, including a lack of renal toxicity, patients with UBC, who are often older and have a higher incidence of renal impairment, may be better able to tolerate MPDL3280A versus chemotherapy. These results suggest that MPDL3280A may have an important role in treating UBC-the drug received breakthrough designation status by the US Food and Drug Administration (FDA) in June 2014.

MPDL3280A (anti-PD-L1) treatment leads to clinical activity in metastatic bladder cancer

Targeted Disruption of the MyD88 Gene Results in Loss of IL-1- and IL-18-Mediated Function

Since its conception two decades ago, the Th1-Th2 paradigm has provided a framework for understanding T cell biology and the interplay of innate and adaptive immunity. Naive T cells differentiate into effector T cells with enhanced functional potential for orchestrating pathogen clearance largely under the guidance of cytokines produced by cells of the innate immune system that have been activated by recognition of those pathogens. This secondary education of post-thymic T cells provides a mechanism for appropriately matching adaptive immunity to frontline cues of the innate immune system. Owing in part to the rapid identification of novel cytokines of the IL-17 and IL-12 families using database searches, the factors that specify differentiation of a new effector T cell lineage-Th17-have now been identified, providing a new arm of adaptive immunity and presenting a unifying model that can explain many heretofore confusing aspects of immune regulation, immune pathogenesis, and host defense.

IL-17 Family Cytokines and the Expanding Diversity of Effector T Cell Lineages

The mechanism underlying the differentiation of CD4+ T cells into functionally distinct subsets (Th1 and Th2) is incompletely understood, and hitherto unidentified cytokines may be required for the functional maturation of these cells. Here we report the cloning of a recently identified IFN-gamma-inducing factor (IGIF) that augments natural killer (NK) activity in spleen cells. The gene encodes a precursor protein of 192 amino acids and a mature protein of 157 amino acids, which have no obvious similarities to any peptide in the databases. Messenger RNAs for IGIF and interleukin-12 (IL-12) are readily detected in Kupffer cells and activated macrophages. Recombinant IGIF induces IFN-gamma more potently than does IL-12, apparently through a separate pathway. Administration of anti-IGIF antibodies prevents liver damage in mice inoculated with Propionibacterium acnes and challenged with lipopolysaccharide, which induces toxic shock. IGIF may be involved in the development of Th1 cells and also in mechanisms of tissue injury in inflammatory reactions.

Cloning of a new cytokine that induces IFN-gamma production by T cells.

Administration of monoclonal anti-CD3 antibody to mice treated with Propionibacterium acnes induced secretion of a high level of gamma interferon (IFN-gamma) into the circulation system, while it induced no significant release in untreated mice. In order to analyze this high-level induction of IFN-gamma in these bacterium-treated mice, we investigated the factors that might be involved. An activity that induces IFN-gamma in T cells was observed in the liver extracts of mice treated with P. acnes and subsequently challenged with lipopolysaccharide. Here, we purified an IFN-gamma-inducing factor from the liver extract to homogeneity and characterized it. Its molecular mass was 18 to 19 kDa, and its pI was 4.9. The amino acid sequence of the NH2-terminal portion was determined and shown to have no similarities to any protein in the EMBL, GenBank, and PIR data bases. The same molecule was also demonstrated in the serum factor that was previously reported to have an IFN-gamma-inducing activity and to have an apparent molecular mass of 75 kDa. Moreover, the activity of this serum factor was recovered in the fraction containing the 18- to 19-kDa protein under reducing conditions and was shown to have the same NH2-terminal amino acid sequence as that of the factor from the liver extract. In addition to the ability to induce IFN-gamma, this protein augmented T-cell proliferation and NK activity in the spleen cells. Thus, several of its biological activities were apparently similar to those of interleukin-12. These results indicated that this novel protein, which exhibited marked costimulatory activity on IFN-gamma production in vitro, was elevated vivo in response to P. acnes treatment. This factor, probably released from the producing cells by lipopolysaccharide stimuli, may be involved in the high-level induction of IFN-gamma in the P. acnes-treated mice.

T Komatsu

Papers

Cloning of a new cytokine that induces IFN-gamma production by T cells.

A novel costimulatory factor for gamma interferon induction found in the livers of mice causes endotoxic shock.