We have established a murine model system for exploring the ability of a CD4 subset-deficient host to cope with cytomegalovirus infection, and reported three findings. First, an antiviral response of the CD8 subset of T lymphocytes could be not only initiated but also maintained for a long period of time despite a continued absence of the CD4 subset, whereas the production of antiviral antibody proved strictly dependent upon help provided by the CD4 subset. Second, no function in the defense against infection could be ascribed as yet to CD4-CD8- T lymphocytes, which were seen to accumulate to a new subset as a result of depletion of the CD4 subset. This newly arising subset did not substitute for CD4+ T lymphocytes in providing help to B lymphocytes, and was also not effective in controlling the spread of virus in host tissues. As long as a function of these cells in the generation and maintenance of a CD8 subset-mediated response is not disproved, caution is indicated with concern to an autonomy of the CD8 subset. Third, even though with delay, the CD8+ effector cells raised in the CD4 subset-deficient host were able of clear vital tissues from productive infection and to restrict asymptomatic, persistent infection to acinar glandular epithelial cells in salivary gland tissue.

https://rupress.org/jem/article-pdf/169/4/1199/1098943/1199.pdf

Site-restricted persistent cytomegalovirus infection after selective long-term depletion of CD4+ T lymphocytes.

Large-scale sequence analysis of the AD169 strain of human cytomegalovirus (HCMV) began in this laboratory in 1984 when very little was known about the sequence or location of genetic information in the viral genome. At that time sequence analysis was confined to the major immediate-early gene (Stenberg et al. 1984), a region of the Colburn strain that contained CA tracts (Jeang and Hayward 1983), the L-S junction region (Tamashiro et al. 1984), and what has been termed the transforming region (Kouzarides et al. 1983). This chapter is being written in March 1989 when the sequence is complete except for some remaining polishing of certain areas which is still going on (manuscript in preparation). As far as we know there are no major discrepancies in the data which might lead to the sequence changing although of course this cannot be ruled out. We present a preliminary analysis of the HCMV genome and limit ourselves mainly to the potential protein-coding content of over 200 reading frames.

Analysis of the Protein-Coding Content of the Sequence of Human Cytomegalovirus Strain AD169

Biology and clinical relevance of human natural killer cells.

The vast majority of mature T lymphocytes in the peripheral blood and lymphoid organs use the CD3-associated alpha, beta T-cell receptor (TCR) heterodimer for antigen recognition. A second class of TCRs consists of disulphide-linked gamma and delta proteins that are also CD3-associated. A subset of early CD3+ fetal and adult CD4- 8- thymocytes express gamma, delta TCRs before alpha, beta TCRs are detectable. In addition, a minor (1-5%) subpopulation of peripheral T lymphocytes, and some spleen cells from nude mice express gamma, delta TCRs. Notably, dendritic epidermal cells have also been shown to express gamma, delta TCRs. All of these populations lack CD4 and CD8 molecules. We now report that most mature T cells residing in the murine intestinal epithelium express CD3-associated TCRs composed of gamma-chains disulphide-linked to a protein resembling the delta-chain. The striking feature of these intraepithelial lymphocytes (IEL) was that they were exclusively CD4-8+. In addition, approximately half of CD3-bearing IEL lacked detectable Thy-1 on the cell surface, which is unprecedented for murine T cells. In contrast to other CD8+ peripheral T cells, freshly isolated IEL could be induced to display cytolytic activity by engaging the CD3 molecule, indicating that activation had occurred in vivo. Thus, CD8+ IEL are a phenotypically diverse and anatomically restricted population of lymphocytes that use gamma-chain containing heterodimers for antigen recognition.

Expression of the γ-δ T-cell receptor on intestinal CD8+ intraepithelial lymphocytes

THE majority of T cells bear the T-cell receptor (TCR) αβ complex which recognizes foreign antigen peptides only in the context of self major histocompatibility complex (MHC) molecules1. Such T cells function in a variety of effector roles and secrete cytokines that mediate the activation and differentiation of other cells in the immune system. Recently, a small subpopulation T cells was found to bear a distinct TCR composed of γ and δ subunits2. In man, TCR γδ+ cells are distributed as ~5 per cent of the CD3+ cells in all organized lymphoid organs as well as in the skin- and gut-associated lymphoid tissues3. Although a limited number of germ-line genes encode the TCR γ and δ subunits, extensive junctional variation particularly in the δ gene, results in unprecedented diversity for this receptor4,5 The nature of the specificity and immunological functions of these T cells remains enigmatic. We report here that in contrast to the normal low frequency of γδ-bearing cells in lymphoid tissues, peripheral blood, or normal skin, the frequency is increased five to eightfold in particular granulomatous reactions of leprosy. TCR γδ+lymphocyte lines from these leprosy skin lesions proliferate in vitro specifically to mycobacterial antigens. This reactivity to foreign antigens appears to require presentation in the context of self-molecules. Moreover, culture supernatants from activated γδT lymphocytes induce adhesion and aggregation of bone-marrow monocytes in the presence of granulocyte monocyte-colony stimulating factor (CSF), suggesting that products of γδ-bearing T cells may play a role in the immune response, possibly by stimulating granuloma formation.

Lymphocytes bearing antigen-specific γδ T-cell receptors accumulate in human infectious disease lesions

Cloned blood lymphocytes that do not express the α- and β-chains of the T-cell receptor show MHC-unrestricted cytotoxicity. These cells carry the γ-protein, disulphide-linked either to another molecule or to itself, and associated with the CD3 complex. These observations may help to solve the mystery posed by the discovery of the γ gene.

A T-cell receptor gamma/CD3 complex found on cloned functional lymphocytes.

• Background. —Previous studies have shown that peripheral blood involvement is a poor prognostic sign in patients with cutaneous T-cell lymphoma. However, evaluation of the results of these studies is difficult. In this study peripheral blood mononuclear cells from 45 patients with various stages of mycosis fungoides (MF) were investigated for the presence of clonal T-cell populations by T-cell receptor β (TCRβ)-gene rearrangement analysis. Results. —Clonal TCRβ-gene rearrangements were found in five (11%) of 45 patients with MF, including one (3%) of 31 patients without MF and four (27%) of 15 patients with histologically confirmed lymph node involvement. With respect to skin stage, clonal T-cell populations were detected in one (4%) of 23 patients with plaque stage disease, two (10%) of 19 patients with tumor stage disease, and two (50%) of four patients with erythrodermic MF. In the group of patients with lymph node involvement the median survival of patients with detectable clonal T-cell rearrangements in the periphera blood was much shorter (3 months) than that of patients without clonal rearrangements (16 months). Conclusions. —The results of this study indicate that clonal TCRβ-gene rearrangements, as detected by Southem blot analysis, are uncommon in the peripheral blood of [ill] tients with MF, in particular in patients without histologically documented lymph node involvement. The presence [ill] clonal T-cell populations in the peripheral blood of [ill] patients with lymph node involvement is usually [ill] with rapidly fatal disease.

Frequency and prognostic significance of clonal T-cell receptor beta-gene rearrangements in the peripheral blood of patients with mycosis fungoides.

Phenotypic and genotypic analysis of large-cell lymphomas, formerly classified as true histiocytic lymphoma: Identification of an unusual group of tumors

Johan W. van Oostveen

Papers

A T-cell receptor gamma/CD3 complex found on cloned functional lymphocytes.

Frequency and prognostic significance of clonal T-cell receptor beta-gene rearrangements in the peripheral blood of patients with mycosis fungoides.

Phenotypic and genotypic analysis of large-cell lymphomas, formerly classified as true histiocytic lymphoma: Identification of an unusual group of tumors

Remission of monoclonal chronic T-cell expansion associated with severe anemia.