Publisher Summary This chapter focuses on the important discovery that virus-specific cytotoxic T cells are dually specific for virus and for a self cell surface antigen encoded by the major histocompatibility complex (MHC). The initial work was carried out on the lymphocytic choriomeningitis virus system but it soon became evident that the same phenomenon applied to many other viruses. In addition, the same principle has been found to hold for other antigenic systems, such as trinitrophenyl coupled to cells, minor histocompatibility antigens, and the H-Y model. Graft rejection and the need for genetically homogeneous inbred mouse strains for cancer research led to the development of transplantation immunology and immunogenetics. The result is that the gene complex coding for major transplantation antigens is one of the better understood mammalian genetic regions. Cytotoxic T-cell specificity is comparable to serological specificity. Because quantification of specificity or cross-reactivity is difficult, and because of the technical limitations of these cytotoxic T-cell assays, results are interpreted with great reservation. MHC restriction reflects the fact that the effector function of T cells is determined by the kind of Self-H recognized together with the foreign antigen on cell surfaces: K and D are receptors for lytic signals, I determinants are receptors for cell differentiation signals that are delivered antigen-specifically by T cells.

MHC-restricted cytotoxic T cells: studies on the biological role of polymorphic major transplantation antigens determining T-cell restriction-specificity, function, and responsiveness.

▪ Abstract Microglia are the principal immune cells in the central nervous system (CNS) and have a critical role in host defense against invading microorganisms and neoplastic cells. However, as with immune cells in other organs, microglia may play a dual role, amplifying the effects of inflammation and mediating cellular degeneration as well as protecting the CNS. In entities like human immunodeficiency virus (HIV) infection of the nervous system, microglia are also critical to viral persistence. In this review we discuss the role of microglia in three diseases in which their activity is at least partially deleterious: HIV, multiple sclerosis, and Alzheimer's disease.

Microglia as mediators of inflammatory and degenerative diseases.

The macrophage is well established as a target of HIV and simian immunodeficiency virus (SIV) infection and a major contributor to the neuropathogenesis of AIDS. However, the identification of distinct subpopulations of monocyte/macrophages that carry virus to the brain and that sustain infection within the central nervous system (CNS) has not been examined. We demonstrate that the perivascular macrophage and not the parenchymal microglia is the primary cell productively infected by SIV. We further demonstrate that although productive viral infection of the CNS occurs early, thereafter it is not easily detectable until terminal AIDS. The biology of perivascular macrophages, including their rate of turnover and replacement by peripheral blood monocytes, may explain the timing of neuroinvasion, disappearance, and reappearance of virus in the CNS, and questions the ability of the brain to function as a reservoir for productive infection by HIV/SIV.

https://rupress.org/jem/article-pdf/193/8/905/1134352/001885.pdf

Perivascular Macrophages Are the Primary Cell Type Productively Infected by Simian Immunodeficiency Virus in the Brains of Macaques: Implications for the Neuropathogenesis of AIDS

Molecular mechanisms of microglial activation.

To evaluate the presence and distribution of central nervous system infection by human immunodeficiency virus type 1 (HIV-1), we used immunohistochemical methods to map the HIV-1 p24 core protein in the brains of 55 autopsied patients with acquired immunodeficiency syndrome (AIDS). In a subset of 40 of these patients who had undergone antemortem neurological evaluation of the AIDS dementia complex (ADC), we analyzed the relation between the severities of the viral infection and clinical dysfunction. Viral antigen was detected in macrophages and cells with morphological and immunohistochemical characteristics of microglia as well as multinucleated cells. The distribution of antigen-positive cells preferentially involved certain deep brain structures, especially the globus pallidus, other basal ganglia nuclei, and the central white matter. Overall, the presence and frequency of infected cells were highly correlated with the histological findings of multinucleated-cell encephalitis and in general with the clinical ADC stage. However, infection was often more limited than might be "anticipated" from the severity of patients' clinical dysfunction: Only 61% of patients with at least ADC stage 1 had detectable antigen and of these only approximately 30% of the brain sections were antigen positive. These results suggest a pathogenetic model of ADC where virus- or cell-coded toxins amplify the effect of limited brain infection.

AIDS dementia complex and HIV-1 brain infection : clinical-virological correlations

The relationship between HLA determinants on effector and target cells and cell-mediated cytotoxicity was studied using the release of 51Cr from measles virus-infected PHA-blasts. HLA compatibility between effector and target cells was not required if effector lymphocytes were derived from measles seropositive adults, from a patient with SSPE, and from children after live measles vaccination. Cytotoxicity was always abolished after removal of Fc receptor-bearing lymphoid cells. In these donors, the effect is, therefore, probably due to K cells. In contrast, lymphocytes from children with acute measles preferentially killed those virus-infected target cells with which they shared HLA antigens. Selective lytic activity was still observed after elimination of Fc receptor-bearing lymphoid cells. It is suggested that HLA-dependent killer cells represent specific cytotoxic T lymphocytes. These cells seem to be limited to the acute phase of measles.

Demonstration of HLA restricted killer cells in patients with acute measles.

In acquired immunodeficiency syndrome, the lesions of the central nervous system in association with the human immunodeficiency virus are thought to be related to an infection of microglia, although no studies are available in which cultured and physiological characteristics of microglia cells infected in vivo have been examined. In this report, we used brain tissue from a child dying of human immunodeficiency virus infection and show that microglia cells were the main cell population being infected. Moreover, isolated macrophage-like cells from fresh brain material revealed a close resemblance to peripheral blood macrophages in their content of surface and intracellular antigens. No virus particles or viral antigens were produced by these cells during the first week of cultivation. Productive infection was readily apparent, however, by day 30. This finding illustrates the slow nature of the virus life cycle in these cells and the minimal cytopathology that accompanied the infection.

Human immunodeficiency virus infection in microglia: Correlation between cells infected in the brain and cells cultured from infectious brain tissue

An analysis of subacute sclerosing panencephalitis (SSPE) lymphocytes was performed in order to find out whether T or K cells were involved in killing of 51 Cr-labeled allogeneic measles virus-infected target cells. Lymphocyte donors were three patients with SSPE, 10 measles seropositive controls and 2 children with measles rash. It was found that about 75% of measles-specific cytotoxicity was lost after removal of Fc-receptor-bearing cells by adsorption onto immune complex monolayers. K cell activity (as measured by lysis of 51 Cr-labeled-sensitized chicken red blood cells) was reduced to the same extent. After adsorption, the enhancing effect by specific antibody was no longer observed. Unfractionated peripheral lymphoid cells that had been treated with pronase and kept in culture 24 hr were inactive in the cytotoxicity test when compared to freshly isolated cells. However, cytotoxicity could be restored almost completely by the addition of measles antibodies. The results indicate that measles-specific cytotoxicity by peripheral lymphoid cells from all three groups of donors is mediated by K cells. It is probable that specificity is provided by a small amount of contaminating serum antibody or immune complexes.

Cell-Mediated Cytotoxicity Against Measles Virus in SSPE II. Analysis of Cytotoxic Effector Cells

Pretreatment of SSPE peripheral lymphoid cells by serum or CSF neither blocked nor increased measles-specific cytotoxicity when cells were subsequently tested in FCS containing tissue culture medium. However, killing activity was always enhanced after pretreatment of target cells or direct addition of serum or CSF to the cytotoxic assay. Enhancement was also observed with non-SSPE-derived measles antibodies. The effect was dependent on measles antibody concentrations. These results suggest that antibody-dependent killing by K cells is intact in patients with SSPE. It is possible that virus-infected brain cells are protected from an immune attack in vivo by antibody-induced antigenic modulation.

Cell-Mediated Cytotoxicity Against Measles Virus in SSPE I. Enhancement by Antibody

In vivo andin vitro tests were performed to detect any immunological abnormalities in SSPE patients (n=15). An unexpected high incidence of skin test anergy (about 40%) against 5 common skin test antigens was observed (candidin, streptokinase-streptodornase, mumps, PPD, trichophytin). All of these patients could, however, be successfully sensitized to 2,4-dinitrochlorbenzene (DNCB).

H. W. Kreth

Papers

Demonstration of HLA restricted killer cells in patients with acute measles.

Human immunodeficiency virus infection in microglia: Correlation between cells infected in the brain and cells cultured from infectious brain tissue

Cell-Mediated Cytotoxicity Against Measles Virus in SSPE II. Analysis of Cytotoxic Effector Cells

Cell-Mediated Cytotoxicity Against Measles Virus in SSPE I. Enhancement by Antibody

Cellular immunity in SSPE patients.