The last ten years have seen an explosive growth in our understanding of IFN gamma. The cloning of the cDNAs for IFN gamma and its receptor have made available large amounts of highly purified recombinant IFN gamma and soluble IFN gamma receptor. In addition, highly specific neutralizing monoclonal antibodies have been generated to both of these proteins. Using these reagents, IFN gamma and the IFN gamma receptor have been characterized on a molecular basis. Structure-function studies carried out on these proteins have identified key molecular regions that are required for biologic activity. Moreover, a great deal is now known concerning the physiologic role that IFN gamma plays in vivo. In this review we focus on the new developments in the areas of IFN gamma biochemistry and biology and pay particular attention to the IFN gamma receptor and three aspects of IFN gamma biology that are of special interest to immunologists: host defense, inflammation, and autoimmunity.

/pdf/the-molecular-cell-biology-of-interferon-gamma-and-its-3by8w0vlph.pdf

The Molecular Cell Biology of Interferon-gamma and its Receptor

In the past few years, there has been a virtual explosion of information on the viral and bacterial molecules now known as superantigens. Some structures have been defined and the mechanism by which they interact with MHC class II and the V beta region of the T cell receptor is being clarified. Data are accumulating regarding the importance of virally encoded superantigens in infectivity, viral replication, and the life cycle of the virus. In the case of MMTV, evidence also suggests that superantigens encoded by a provirus may be maintained by the host to protect against future exogenous MMTV infection. Experiments in animals have also begun to elucidate the dramatic and variable effects of superantigens on responding T cells and other immune processes. Finally, the role of superantigens in certain human diseases such as toxic shock syndrome, some autoimmune diseases like Kawasaki syndrome, and perhaps some immunodeficiency disease such as that secondary to HIV infection is being addressed and mechanisms are being defined. Still, numerous important questions remain. For example, it is not clear how superantigens with such different structures, for example, SEB, TSST-1, and MMTV vSAG, can interact with MHC and a similar region of the TCR in such basically similar ways. It remains to be determined whether there are human equivalents of the endogenous murine MMTV superantigens. The functional role of bacterial superantigens also remains to be explained. Serious infection and serious consequences from toxin-producing bacteria are relatively rare events, and it is questionable whether such events are involved in the selection pressure to maintain production of a functional superantigen. Hypotheses to explain these molecules, which can differ greatly in structure, include T cell stimulation-mediated suppression of host responses or enhancement of environments for bacterial growth and replication, but substantiating data for these ideas are mostly absent. It also seems likely that only the tip of the iceberg has been uncovered in terms of the role of superantigens in human disease. Unlike toxic shock syndrome, other associations, especially with viral superantigens, may be quite subtle and defined only after considerable effort. The definition of these molecules and mechanisms of disease may result in new therapeutic strategies. Finally, it is apparent that superantigens have dramatic effects on the immune system. One wonders whether these molecules or modifications of them can be used as specific modulators of the immune system to treat disease.

Superantigens and their potential role in human disease.

Intracellular Cytokine Profile of Cord and Adult Blood Lymphocytes

Superantigens are unique products of bacteria and viruses which, in combination with class II major histocompatibility complex molecules, are capable of stimulating a large fraction of T cells in an affected individual. This stimulation primarily involves the variable region of the T cell receptor beta chain (Vβ). The discovery of superantigens and the elucidation of their immunologic properties have provided valuable tools for the investigation of the immune system in both normal and diseased animals. Most importantly, recent work suggests that superantigens play a role in a number of diverse pathological conditions, including toxic shock syndrome and autoimmune diseases such as rheumatoid arthritis.

Superantigens: biology, immunology, and potential role in disease.

Different “professional” antigen-presenting cells (APC) have unique characteristics that favor or restrict presentation of microbial antigens to T cells, depending on the organism. Cryptococcus neoformans is a pathogenic yeast that presents unique challenges to APC, including its large size, its rigid cell wall, and its ability to stimulate T cells as a mitogen. T-cell proliferation in response to the C. neoformans mitogen (CnM) requires phagocytosis and processing of the organisms by accessory cells prior to presentation of CnM to T cells. Because of the requirement for uptake of the organism and more limited costimulatory requirements of mitogens, macrophages might be the most likely cellular source for the accessory cell. However, the present study demonstrates that a transiently adherent cell that was CD3−, CD14−, CD19−, CD56−, HLA-DR+, and CD83+ with a dendritic morphology, rather than monocyte-derived or tissue (alveolar) macrophages, was the most efficient APC for presentation of CnM. A large number of these cells bound and internalized the organism, and only a small number of dendritic cells were required for presentation of the mitogen to T cells. Further, the mannose receptor and Fcγ receptor II were required for presentation of C. neoformans, as blocking either of these receptors abrogated both uptake of C. neoformans and lymphocyte proliferation in response to CnM. These studies demonstrate the surprising fact that dendritic cells are the most efficient accessory cells for CnM.

https://iai.asm.org/content/iai/70/11/5972.full.pdf

Primary Dendritic Cells Phagocytose Cryptococcus neoformans via Mannose Receptors and Fcγ Receptor II for Presentation to T Lymphocytes

Administration of interferon-γ (IFN-γ) provides a new approach to the treatment of tumors and viral and microbial infections. The aim of this study was to evaluate the pharmacokinetics of recombinant murine IFN-γ (rMuIFN-γ) in the mouse system as a model for future investigations of the therapeutical effect of IFN-γ. After a bolus injection of 2 × 104 LU/mouse by the intravenous (i.v.) route, a biphasical elimination pattern of the antiviral activity from the serum was detected in female and male C57BL/6 and CBA/2 mice with a β half-life time of 19-32 min. After intramuscular (i.m.) and subcutaneous (s.c.) injection of rIFN-γ, antiviral activity in serum could be detected from 30 to 270 min after the bolus application. There was a plateau in the activity from 65 to 135 min after s.c. and from 84 to 143 min after i.m. injection. Both kinetics fit with a pharmacokinetic model of biphasical elimination with an entrance compartment.

Pharmacokinetics of Recombinant Murine Interferon-γ in Mice

The placenta plays an important role in protecting the fetus from maternal infections and in preventing an effective immune response of the mother against the fetus. We compared lymphokine production by human placental leukocytes with that of adult and cord blood leukocytes. Decidual and adult blood lymphocytes synthesized comparable quantities of interferon-γ (IFN-γ) following incubation with phytohemagglutinin (PHA). In contrast, lymphocytes of cord blood and fetal placental tissue stimulated with PHA produced very low titers of IFN-γ. This defect was less marked after stimulation with staphylococcus enterotoxin B (SEB). In the presence of SEB, cord blood cells produced interleukin-2 (IL-2) and significant amounts of IFN-γ. Production of IL-4 could not be detected. Collectively, these results indicate that fetal T lymphocytes show certain defects of lymphokine production.

Interferon and lymphokine production by human placental and cord blood cells.

Mycoplasma arthritidis produces in culture a polyclonal mitogen which is active for murine and human T lymphocytes in the presence of accessory cells (AC). We studied the requirements for processing and presentation by AC of Mycoplasma arthritidis supernatant (MAS) mitogen to human T cells. As inhibitors of AC processing, several agents were used which inhibit lysosomal function: the weak bases chloroquine and NH4Cl, the cationic ionophore monensin and the competitive protease inhibitor leupeptin. When these agents were used to inhibit processing by presenting cells and washed out before T cells were added to culture, they inhibited lymphocyte activation and, therefore, we assume that they interfered with the presentation of the mitogen. Thus, if MAS requires a processing step, it appears to involve lysosomal proteolysis which can be blocked in vitro.

Processing requirements for T cell activation by Mycoplasma arthritidis‐derived mitogen

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Pharmacokinetics of Recombinant Murine Interferon-γ in Mice

Interferon and lymphokine production by human placental and cord blood cells.

Processing requirements for T cell activation by Mycoplasma arthritidis‐derived mitogen