The effects of human cytomegalovirus challenge in vitro on subpopulations of T cells from seronegative donors

Abstract

Purified T cells from seronegative donors were challenged with human cytomegalovirus (CMV) and assayed for response to the mitogen phytohemagglutinin (PHA) administered at various times after virus challenge. Cells were hyporesponsive to PHA added up to 6 h postinfection, while cells challenged with ultraviolet (UV)-inactivated CMV showed normal PHA responses. T-cell populations showed a complete inversion of helper/suppressor ratios by 6 h of infection, as determined by indirect immunofluorescence using the monoclonal antibodies OKT4 and OKT8. This increased proportion of suppressor cells was functionally demonstrable in an autologous one-way mixed lymphocyte reaction (AMLR).

The immunosuppressive effect of human cytomegalovirus infection in recipients of allogeneic hematopoietic stem cell transplantation

“…Decrease of T-cell proliferative response to mitogens, as well as decreased ability to produce pro-inflammatory cytokines, was first described in immune-competent individuals with HCMV mononucleosis. 7,8 The effect could be observed as soon as 6 h after exposure 24 and declined with convalescence. 7 Although experimental data suggested the role of a humoral factor produced by the virus, 24 this could not be identified for many years until the recent discovery by Kotenko et al 9 , who demonstrated that human HCMV encodes a homologue of IL-10.…”

“…7,8 The effect could be observed as soon as 6 h after exposure 24 and declined with convalescence. 7 Although experimental data suggested the role of a humoral factor produced by the virus, 24 this could not be identified for many years until the recent discovery by Kotenko et al 9 , who demonstrated that human HCMV encodes a homologue of IL-10. Despite only 27% identity with human IL-10, this virus-encoded protein has high affinity for human IL-10 receptor 1.…”

Recent clinical isolates of cytomegalovirus suppress human cytomegalovirus-specific human leukocyte antigen-restricted cytotoxic T-lymphocyte activity

“…Interleukin II was added on day 6, and cultures were tested for cytotoxicity on day 12. b See Table 1, footnote b. HCMV-induced suppression is specific to HCMV CTLs or affects other viral CTL responses as well. However, in other experiments it has been shown that HCMV can suppress not only T-cell proliferation to HCMV (R. Schrier, unpublished observations), but also to herpes simplex virus and mitogens (17,23). HCMV can infect lymphocytes and monocytes, but only a fraction (average, 2%; range, 0 to 15%) of the population shows viral nucleic acid or protein (17,23).…”

“…However, in other experiments it has been shown that HCMV can suppress not only T-cell proliferation to HCMV (R. Schrier, unpublished observations), but also to herpes simplex virus and mitogens (17,23). HCMV can infect lymphocytes and monocytes, but only a fraction (average, 2%; range, 0 to 15%) of the population shows viral nucleic acid or protein (17,23). Because of the small numbers of PBM involved, it has been difficult to determine how this fraction mediates suppression and whether these cells are killed by the virus.…”

Human cytomegalovirus infection induces transcription and secretion of transforming growth factor beta 1

“…Infection of peripheral blood leukocytes and endothelial cells by CMV results in enhanced production of IL-13, TNF-ot, gamma interferon, and colony-stimulating factor-1 (12,29,49), as well as labile suppressor factor(s) (8,27,45). Finally, infection of bone marrow cells increases both production of alpha interferon, gamma interferon, TNF-ao (7,23,32,33,37,38), and IL-6 and transcription of basic fibroblast growth factor (11,12,22) but transiently suppresses IL-lox and production (48).…”