Significance of herpesvirus immediate early gene expression in cellular immunity to cytomegalovirus infection

Reddehase, Matthias J.; Koszinowski, Ulrich H.

doi:10.1038/312369a0

Cited by 160 publications

(140 citation statements)

References 34 publications

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“…Our data suggest that infants are capable of generating IE1-specific CD8 ϩ T cell responses, and that IE1 may be more commonly targeted by CD8 ϩ T cells. The apparent prominence of IE1-specific CD8 ϩ T cell responses over time is compatible with the reported immunogenicity of IE1 in mice (58,59) and humans (26). Moreover, culture-based methodologies used in early studies to identify targets of HCMV-specific CD8 ϩ T cell responses may have preferentially expanded pp65-specific CD8 ϩ T cells (55).…”

Section: Discussionsupporting

confidence: 52%

Human Cytomegalovirus Proteins pp65 and Immediate Early Protein 1 Are Common Targets for CD8+ T Cell Responses in Children with Congenital or Postnatal Human Cytomegalovirus Infection

Gibson

Piccinini²,

Lilleri³

et al. 2004

The Journal of Immunology

106

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Recombinant modified vaccinia Ankara- and peptide-based IFN-γ ELISPOT assays were used to detect and measure human CMV (HCMV)-specific CD8+ T cell responses to the pp65 (UL83) and immediate early protein 1 (IE1; UL123) gene products in 16 HCMV-infected infants and children. Age at study ranged from birth to 2 years. HCMV-specific CD8+ T cells were detected in 14 (88%) of 16 children at frequencies ranging from 60 to >2000 spots/million PBMC. Responses were detected as early as 1 day of age in infants with documented congenital infection. Nine children responded to both pp65 and IE1, whereas responses to pp65 or IE1 alone were detected in three and two children, respectively. Regardless of the specificity of initial responses, IE1-specific responses predominated by 1 year of age. Changes in HCMV epitopes targeted by the CD8+ T cell responses were observed over time; epitopes commonly recognized by HLA-A2+ adults with latent HCMV infection did not fully account for responses detected in early childhood. Finally, the detection of HCMV-specific CD8+ T cell responses was temporally associated with a decrease in peripheral blood HCMV load. Taken altogether, these data demonstrate that the fetus and young infant can generate virus-specific CD8+ T cell responses. Changes observed in the protein and epitope-specificity of HCMV-specific CD8+ T cells over time are consistent with those observed after other primary viral infections. The temporal association between the detection of HCMV-specific CD8+ T cell responses and the reduction in blood HCMV load supports the importance of CD8+ T cells in controlling primary HCMV viremia.

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Section: Discussionsupporting

confidence: 52%

Human Cytomegalovirus Proteins pp65 and Immediate Early Protein 1 Are Common Targets for CD8+ T Cell Responses in Children with Congenital or Postnatal Human Cytomegalovirus Infection

Gibson

Piccinini²,

Lilleri³

et al. 2004

The Journal of Immunology

106

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“…However, Glorioso et al (1985) have shown that gC is the major target antigen recognized by MHC class I restricted T cells. This is particularly intriguing in view of the evidence in other viruses where there is a dominant recognition of nonmembrane proteins, such as nucleoprotein of influenza (Townsend et al, 1984), immediate early gene product of murine cytomegalovirus (Reddehase & Koszinowski, 1984), and the nuclear protein of vesicular stomatitis virus (Yewdell et al, 1986). It remains to be determined conclusively which is the dominant antigen recognized by HSV-l-specific CTLs.…”

Section: Discussionmentioning

confidence: 85%

Specificity of the Immune Response of Mice to Herpes Simplex Virus Glycoproteins B and D Constitutively Expressed on L Cell Lines

Blacklaws

Nash

Darby

1987

Journal of General Virology

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SUMMARYMouse L cell lines have been developed which constitutively express glycoproteins B (gB) and D (gD) of herpes simplex virus type 1. When used to study the immune response of mice to the viral glycoproteins, it was found that both gB and gD induce a delayed type hypersensitivity response and both also induce an antibody response, but only the cell line expressing gD could stimulate the production of neutralizing antibody. Virus-specific cytotoxic T lymphocytes (CTLs) recognized gB expressed by the cell line and this line could also induce CTLs in mice. Recognition of gD by major histocompatibility complex class I restricted CTLs was never seen. Vaccination of mice with the cell lines provided protection from viral challenge and inhibited the establishment of a latent infection, although gD proved to be the better protective immunogen. INTRODUCTIONThe immune response of mice to herpes simplex virus type 1 (HSV-1) is known to involve both antibody and cell-mediated protective mechanisms. In particular, T lymphocytes are considered to play a central role in the recovery from a primary infection (for review, see Nash et al., 1985). However, the particular proteins of the virus recognized by these cells are far from clear. Experiments to date have centred on the use of the virus mutants deficient in the expression of certain glycoproteins to study the nature of the antigens recognized by cytotoxic T lymphocytes (CTLs) (Carter et al., 1981;Lawman et al., 1980;Glorioso et al., 1985), and the affinity purification of glycoproteins from whole virus preparations for use as immunogens to study delayed type hypersensitivity (DTH) responses (Schrier et al., 1983;Chan et al., 1985).The main problem has been how to separate the various antigens of this complex virus in order to dissect the nature of the immune response. Our approach has been to investigate the immune response to individual glycoproteins of HSV-1 by expressing the appropriate genes in mouse L cells. In this system, the glycoproteins are expressed in isolation but are still presented at the cell surface analogous to infected cells. Our reason for choosing glycoproteins is that they are likely to represent major target antigens of the immune system: this is true for the antibody response (for review, see Norrild, 1985) and there is evidence to suggest that glycoproteins are the major targets for both major histocompatibility complex (MHC) class I and class II restricted T lymphocytes (Carter et al., 1981 ;Lawman et al., 1980;Glorioso et al., 1985;Schrier et al., 1983).In this paper we report the establishment of L cells expressing either glycoprotein B (gB) or D (gD) and the use of these lines to study the specificity of the T cell response to HSV-1. The lines were also used to immunize mice against primary virus infections and to prevent the establishment of latent infections.

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“…Cytotoxic T cells generated in vivo during MCMV infection are specific for cells that express immediate early proteins in assays in vitro (Reddehase & Kosinowski, 1984;Reddehase et al, 1984a, b). However, the primary cytotoxic response in the animal cannot be easily detected by assays in vitro and requires a further step of incubation of lymphocytes from infected mice with IL-2 in vitro (Reddehase & Koszinowski, 1984;Sinickas et al, 1985a, b). This observation raises uncertainty concerning the usefulness of assays in vitro for the detection of cytotoxic T cells involved in immunity against herpesviruses.…”

Section: Discussionmentioning

confidence: 93%

“…The infection of mice with murine cytomegalovirus (MCMV) elicits the production of T cells which proliferate (Howard et al, 1978) or produce lymphokines (Sinickas et al, 1985 c) following re-exposure to MCMV in vitro ; they lyse virus-infected target cells in vitro (Ho, 1980;Reddehase & Koszinowski, 1984;Sinickas et al, 1985a, b) or mount delayed-type hypersensitivity (DTH) responses in vivo (Chong & Mires, 1982). Although the relative importance of T cell-mediated responses compared with other host protective mechanisms remains to be determined, T cells are important in regulating the course of primary MCMV infection since nude mice show 1" Present address: Department of Virology, Royal Free Hospital, Hampstead, London, U.K.…”

Section: Introductionmentioning

confidence: 99%

Delayed-type Hypersensitivity Responses to Murine Cytomegalovirus in Genetically Resistant and Susceptible Strains of Mice

Lawson

Grundy

Shellam

1987

Journal of General Virology

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SUMMARYThe delayed-type hypersensitivity (DTH) response in mice infected with murine cytomegalovirus (MCMV) was measured by ear swelling following a challenge with heat-treated MCMV. DTH was dose-dependent and could be detected as early as 3 days post-infection with peak responses occurring between days 15 and 21 postinfection. The DTH response was found to be specific for MCMV since it could not be elicited by either herpes simplex virus type 1 or influenza A virus in MCMV-primed mice. The elicited DTH response was greater in mice primed with attenuated compared with virulent MCMV. The DTH response was shown to correlate positively with the genetically determined resistance status of mouse strains to this virus.

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Significance of herpesvirus immediate early gene expression in cellular immunity to cytomegalovirus infection

Cited by 160 publications

References 34 publications

Human Cytomegalovirus Proteins pp65 and Immediate Early Protein 1 Are Common Targets for CD8+ T Cell Responses in Children with Congenital or Postnatal Human Cytomegalovirus Infection

Human Cytomegalovirus Proteins pp65 and Immediate Early Protein 1 Are Common Targets for CD8+ T Cell Responses in Children with Congenital or Postnatal Human Cytomegalovirus Infection

Specificity of the Immune Response of Mice to Herpes Simplex Virus Glycoproteins B and D Constitutively Expressed on L Cell Lines

Delayed-type Hypersensitivity Responses to Murine Cytomegalovirus in Genetically Resistant and Susceptible Strains of Mice

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