Human blood mononuclear leukocytes stimulated with toxoplasma antigen, concanavalin A, mezerein plus lentil lectin, or staphylococcal enterotoxin A secreted a factor (macrophage-activating factor, or MAF) that enhanced the capacity of human macrophages to release H2O2 and to kill toxoplasmas. The same lymphoid supernatants contained IFN gamma but not IFN alpha or IFN beta. The MAF activity of six of seven unfractionated supernatants was completely eliminated by a monoclonal antibody that neutralizes IFN gamma, and MAF in the remaining supernatant was almost completely neutralized. Native IFN gamma partially purified by two independent protocols to specific activities of 1 X 10(6) and 10(7) U/mg protein was enriched in MAF activity at least as much as in antiviral activity. The capacity of macrophages to secrete H2O2 after incubation in partially purified native IFN gamma (mean peak stimulation, 8.8-fold) was greater than with unpurified lymphokines (3.8-fold) and sometimes equaled or exceeded the capacity of freshly harvested monocytes. The MAF activity of the partially purified native IFN gamma preparations was abolished by monoclonal anti-IFN gamma. Finally, IFN gamma of greater than 99% estimated purity was isolated (at Genentech, Inc.) from bacteria transformed with the cloned human gene for this lymphokine. Recombinant IFN gamma had potent MAF activity, stimulating the peroxide-releasing capacity of macrophages an average of 19.8-fold at peak response and enhancing their ability to kill toxoplasmas from 2.6 +/- 1.3% for untreated cells to 54 +/- 0.4% for treated cells. Attainment of 50% of the maximal elevation in peroxide-releasing capacity required a geometric mean concentration of 0.1 antiviral U/ml of recombinant IFN gamma, which is estimated to be approximately 6 picomolar for this preparation. Peroxide secretory capacity and toxoplasmacidal activity of macrophages peaked 2-4 d after exposure to IFN gamma. Peroxide-secretory capacity remained elevated during at least 6 d of continuous exposure, but the effect of IFN gamma was reversed within about 3 d of its removal. Activation was usually but not invariably accompanied by characteristic changes in cell morphology. Thus, IFN gamma activates human macrophage oxidative metabolism and antimicrobial activity, and appeared to be the only factor consistently capable of doing so in the diverse LK preparations tested.

https://rupress.org/jem/article-pdf/158/3/670/1093775/670.pdf

Identification of interferon-gamma as the lymphokine that activates human macrophage oxidative metabolism and antimicrobial activity.

Role of aberrant hla-dr expression and antigen presentation in induction of endocrine autoimmunity

Cells in the brain express unusually low levels of antigens encoded by the major histocompatibility complex (MHC)1,2. This is somewhat surprising as class I (H−2) and class II (Ia) MHC antigens have critical roles in immune responses3. The activation of T lymphocytes is associated with the enhanced expression of these antigens and this effect is mediated by a specific T-cell lymphokine, γ-interferon (IFN-γ)4–17. Here we show that IFN-γ induces a dramatic increase in the expression of H–2 antigens on the cells of the brain. After exposure to IFN-γ in vitro, all surviving cells, including most astrocytes, oligodendrocytes, microglia and at least some neurones, express H–2 antigens. Direct injection of IFN-γ into the brains of mice indicated that H–2 antigens were also induced in vivo. Furthermore, IFN-γ induced Ia antigens on a subpopulation of astrocytes. The induction of H–2 antigens by IFN-γ may render brain cells competent to initiate and participate in immune reactions and may therefore contribute to both immunoprotective and immunopathological responses in the brain.

Inducible expression of H-2 and Ia antigens on brain cells.

We have used monoclonal antibody binding, measured by radioimmunoassay, fluorescence flow cytometry, and ultrastructural immunocytochemistry, to measure expression of Ia antigens on cultured human umbilical vein endothelial (HUVE) cells. Under standard culture conditions, HUVE cells do not express Ia antigens. However, treatment of primary HUVE cultures with phytohemagglutinin induces the expression of Ia antigens. Every endothelial cell in the culture becomes Ia-positive and endothelial cells appear to synthesize Ia. HLA-A,B is concomitantly increased. The expression of Ia appears to be mediated by T cells because (a) pretreatment of primary HUVE cultures with OKT3 plus complement blocks the action of the lectins but not of medium conditioned by lectin-activated peripheral blood mononuclear cells; (b) co-culture of endothelial cells with allogeneic T cells, in the absence of lectin, also induces endothelial Ia; and (c) human immune (gamma) interferon, produced by Chinese hamster ovary cells transfected with the human gamma interferon gene, directly induces endothelial Ia. During co-culture with lymphocytes, about one-third of the endothelial cells are Ia-positive after 24 h and all of the endothelial cells are Ia-positive by 72 h. Proliferation of allogeneic T cells starts by 96 h and peaks at 144 h. Thus, endothelial Ia appears sufficiently early to be a determinant for the proliferation of allogeneic T cells. Inducible expression of Ia by endothelium may be important both for allograft rejection and for recruitment of circulating T cells into the site of an immune response.

https://rupress.org/jem/article-pdf/157/4/1339/1093320/1339.pdf

Ia expression by vascular endothelium is inducible by activated T cells and by human gamma interferon.

Inducible expression of h-2 and ia antigens on brain-cells and pancreatic-islet cells by a t-cell lymphokine, interferon-gamma

This investigation examined the effects of mediators derived form activated spleen cells on macrophage Ia-antigen expression and function. Incubation of adherent thioglycollate-induced murine peritoneal macrophages(> 90% Ia-) with concanavalin A (Con A)-stimulated spleen cell supernate (Con A sup) resulted in a dose-dependent increase in the percentage of Ia-containing (Ia+) phagocytic cells, as detected by antiserum-and-complement-mediated cytotoxicity. The Ia-antigen expression of macrophages incubated with unstimulated spleen cell supernate supplemented with Con A (Control sup) declined. Pretreatment of the macrophages with anti-Ia and complement before addition of the Con A sup did not inhibit subsequent Ia-antigen expression, suggesting that Ia- macropohages were converted to Ia+ cells. These findings were not a result of adsorption of soluble Ia-antigen from the Con A sup, because Ia-antigen expression was detected by an antiserum specific for the haplotype of the macrophages but not that of the allogeneic spleen cells from which the supernate was prepared. Con A sup-cultured macrophages also stimulated the proliferation of allogeneic spleen cells significantly better than Control sup-cultured macrophages in the mixed leukocyte reaction (MLR). Pretreatment of Con A sup-cultured macrophages with anti-Ia and complement before addition of splenic responder cells abrogated their stimulatory capacity, indicating the Ia dependence of the MLR. We hypothesize that regulatory lymphokine(s) can induce both the expression of the Ia+ phenotype by macrophages and the functional capability to stimulate the MLR, and that macrophages lose these capabilities in the absence of such mediator(s).

https://rupress.org/jem/article-pdf/152/6/1734/1091363/1734.pdf

Regulation of murine macrophage Ia-antigen expression by products of activated spleen cells.

The activation of macrophages and lymphocytes is initiated by exogenous stimuli which often are bacterial in origin. Some of the most potent activating agents are bacterial endotoxin lipopoly- saccharide (LPS), antigenic bacterial components and exotoxins. Macrophages and lymphocytes in turn modulate each other’s level of activation through cell contact and/or mediator dependent mechanisms. For example, some macrophage products suppress lymphocyte proliferation and antibody production. These include thymidine, arginase, prostaglandins and oxygen metabolites, as will be discussed by Dr. Hoffeld (8). Conversely, interferon produced by lymphocytes may have suppressive effects on the activity of macrophages (9). In addition, macrophages and lymphocytes stimulate each other in many ways. In this presentation, we will discuss the multiplicity of endogenous pathways by which lymphocytes and macrophages mutually augment each other’s reactions in their effort to eliminate bacteria or other non-self antigens.

Bi-Directional Macrophage-Lymphocyte Interactions Modulate Immune Responses

A culture supernatant of concanavalin A-activated spleen cells (Con A supernatant) induced murine macrophages to express Ia antigens in vitro. Biochemical characterization of the Con A supernatant indicated that the macrophage Ia antigen regulatory activity shares molecular weight, pI, and hydrophobic and affinity characteristics with immune interferon (IFN-gamma). Antiserum to mouse IFN-gamma neutralized both the macrophage Ia antigen regulatory and IFN-gamma bioactivities of the Con A supernatant. Furthermore, both partially purified murine IFN-gamma (10(7) U/mg protein sp act) and IFN-containing culture supernatants of the murine BFS T cell line-induced macrophage Ia antigen expression in vitro. Culture supernatants containing colony-stimulating factor, interleukin 1, interleukin 2, macrophage migration inhibitory factor, and a macrophage-activating activity that were distinct from IFN-gamma did not induce macrophage Ia antigen expression. Taken together, the data indicate that the in vitro expression of Ia antigens on macrophages is regulated by an activity that has the characteristics of interferon.

https://rupress.org/jem/article-pdf/156/6/1780/1093062/1780.pdf

Regulation of murine macrophage Ia antigen expression by a lymphokine with immune interferon activity.

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Regulation of murine macrophage Ia-antigen expression by products of activated spleen cells.

Bi-Directional Macrophage-Lymphocyte Interactions Modulate Immune Responses

Regulation of murine macrophage Ia antigen expression by a lymphokine with immune interferon activity.