Macrophages Escape Inhibition of Major Histocompatibility Complex Class I-Dependent Antigen Presentation by Cytomegalovirus (original) (raw)
Related papers
Frontiers in Immunology
Human cytomegalovirus (HCMV) persistently infects 40-90% of the human population but in the face of a normal immune system, viral spread and dissemination are efficiently controlled thus preventing clinically signs and disease. HCMV-infected hosts produce a remarkably large amount of HCMV-specific CD4 + and CD8 + T cells that can even reach 20-50% of total T memory cells in the elderly. How HCMV may elicit such large and long-lasting T-cell responses in the absence of detectable viremia has not been elucidated yet. Additionally, HCMV is known to encode several gene products that potently inhibit T-cell recognition of infected cells. The best characterized are the four immune evasive US2, US3, US6, and US11 genes that by different mechanisms account for major histocompatibility complex (MHC) class I and class II degradation and intracellular retention in infected cells. By infecting M1 and M2 human macrophages (Mφ) with the wild-type HCMV strain TB40E or a mutant virus deleted of the four immune evasive genes US2, US3, US6, and US11, we demonstrated that human Mφ counteract the inhibitory potential of the US2-11 genes and remain capable to present peptides via MHC class I and class II molecules. Moreover, by sorting the infected and bystander cells, we provide evidence that both infected and bystander Mφ contribute to antigen presentation to CD4 + and CD8 + T cells. The T cells responding to TB40E-infected Mφ show markers of the T effector memory compartment, produce interferon-γ, and express the lytic granule marker CD107a on the cell surface, thus mirroring the HCMV-specific T cells present in healthy seropositive individuals. All together, our findings reveal that human Mφ escape inhibition of MHC-dependent antigen presentation by HCMV and continue to support T cell proliferation and activation after HCMV infection. Taking into account that Mφ are natural targets of HCMV infection and a site of viral reactivation from latency, our findings support the hypothesis that Mφ play crucial roles for the lifelong maintenance and expansion of HCMV-committed T cells in the human host.
Journal of Virology, 2003
Macrophages play an important role in murine cytomegalovirus (MCMV) infection in vivo, both in disseminating infection and in harboring latent virus. MCMV encodes three immune evasion genes (m4, m6, and m152) that interfere with the ability of cytotoxic T cells (CTL) to detect virus-infected fibroblasts, but the efficacy of immune evasion in macrophages has been controversial. Here we show that MCMV immune evasion genes function in H-2b primary bone marrow macrophages (BMMφ) in the same way that they do in fibroblasts. Metabolic labeling experiments showed that class I is retained in the endoplasmic reticulum by MCMV infection and associates with m4/gp34 to a similar extent in fibroblasts and BMMφ. We tested a series of Kb- and Db-restricted CTL clones specific for MCMV early genes against a panel of MCMV wild-type virus and mutants lacking m152, m4, or m6. MCMV immune evasion genes effectively inhibited antigen presentation. m152 appeared sufficient to abolish Db-restricted present...
Journal of Experimental Medicine, 1992
Selective expression of murine cytomegalovirus (MCMV) immediate-early (IE) genes leads to the presentation by the major histocompatibility complex (MHC) class I molecule L a of a peptide derived from MCMV IE protein pp89 (Reddehase, M. J., J. B. Rothbard, and U. H. Koszinowski. 1989. Nature (Lond.). 337:651). Characterization of endogenous antigenic peptides identified the pp89 peptide as the nonapeptide msYPHFMFFNLt76 U. H. Koszinowski. 1991. Cell. 66:1145). Subsequent expression of MCMV early genes prevents presentation of pp89 (del Val, M., K. Mfinch, M. J. Reddehase, and U. H. Koszinowski. 1989. Cell. 58:305). We report on the mechanism by which MCMV early genes interfere with antigen presentation. Expression of the IE promoter-driven bacterial gene lacZ by recombinant MCMV subjected antigen presentation of B-galactosidase to the same control and excluded antigen specificity. The La-dependent presence of naturally processed antigenic peptides also in nonpresenting cells located the inhibitory function subsequent to the step of antigen processing. The finding that during the E phase of MCMV gene expression the MHC class I heavy chain glycosylation remained in an Endo H-sensitive form suggested a block within the endoplasmic reticulum/c/s-Golgi compartment. The failure to present antigenic peptides was explained by a general retention of nascent assembled trimolecular MHC class I complexes. Accordingly, at later stages of infection a significant decrease of surface MHC class I expression was seen, whereas other membrane glycoproteins remained unaffected. Thus, MCMV E genes endow this virus with an effective immune evasion potential. These results also indicate that the formation of the trimolecular complex of MHC dass I heavy chain, ~2-microglobulin, and the finally trimmed peptide is completed before entering the medial-Golgi compartment.
Journal of Virology
Viruses which cause persistence in the naturally infected host are predicted to have evolved immune evasion mechanisms. Human cytomegalovirus (HCMV) causes significant morbidity and mortality in immunocompromised patients yet persists without clinical manifestations in seropositive individuals who have normal immune function. We report that HCMV infection in vitro impairs major histocompatibility complex class I (MHC-I) assembly accompanied by resistance to killing by cytotoxic CD8+ T lymphocytes. Pulse-chase metabolic labelling experiments show that MHC-I complexes continue to be assembled by both uninfected and HCMV-infected cells. However, MHC-I molecules are unstable in HCMV-infected cells and are rapidly broken down. Endoglycosidase H treatment of immunoprecipitates indicates that the breakdown of MHC-I complexes in HCMV-infected cells occurs primarily in a pre-Golgi compartment. Interference with normal MHC-I assembly and expression, if relevant in vivo, may have implications for the restriction of the diversity of the CD8+ cytotoxic T lymphocyte repertoire directed against HCMV antigens and may be an important mechanism of viral persistence.
Latent Murine Cytomegalovirus Infection in Macrophages
Virology, 1997
In this study we show that macrophages (Mf) are latently infected with murine cytomegalovirus (MCMV). After clearance of acute MCMV infection, the predominant form of chronic infection in Balb mice is latency rather than persistence. Peritoneal exudate cells (PECs) from latently infected Balb mice (3-9 months postinfection) contained MCMV genome and reactivatable virus. Adherent cells from both resident and thioglycollate-elicited PECs carried more MCMV DNA (measured by PCR) than nonadherent cells, and were selectively enriched for Mf. FACS sorted F4/80 / Mf contained MCMV DNA, while other FACS sorted cell populations from PECs were never positive for MCMV DNA. MCMV reactivated from FACS sorted F4/ 80 / Mf in 32% of cocultures with murine embryonic fibroblasts (MEFs). Since Mf carry MCMV genome and reactivatable virus, but not lytic virus, they are latently infected with MCMV. We determined the frequency of Mf carrying MCMV genome in PECs (about 1/50,000) using a limiting dilution PCR assay. Using this frequency and estimates of the total amount of MCMV genome in populations, we estimate that latently infected Mf carry 1-10 copies of MCMV genome. To evaluate the origin of latently infected Mf, we compared the frequency of cells carrying MCMV genome in the resident and elicited PECs. The frequency of Mf carrying MCMV DNA was the same in resident and thioglycollate-elicited PECs, despite the fact that there was a ninefold increase in the number of Mf recovered after thioglycollate elicitation. This argued for recruitment of bone marrow-derived Mf (BMMf) carrying MCMV genome into the peritoneum during inflammatory responses. Consistent with this hypothesis, MCMV genome, but not persistent virus, was detected in bone marrow cells from latently infected mice. ᭧ 1997 Academic Press
Here, we show that the HCMV protein US2 causes degradation of two essential proteins in the MHC class II antigen presentation pathway: HLA-DR-α and DM-α. This was unexpected, as US2 has been shown to cause degradation of MHC class I (refs. 5,6), which has only limited homology with class II proteins. Expression of US2 in cells reduced or abolished their ability to present antigen to CD4 + T lymphocytes. Thus, US2 may allow HCMV-infected macrophages to remain relatively 'invisible' to CD4 + T cells, a property that would be important after virus reactivation.
Journal of Virology, 2002
ABSTRACTCD8 T cells are the principal effector cells in the resolution of acute murine cytomegalovirus (mCMV) infection in host organs. This undoubted antiviral and protective in vivo function of CD8 T cells appeared to be inconsistent with immunosubversive strategies of the virus effected by early (E)-phase genesm04,m06, andm152. The so-called immune evasion proteins gp34, gp48, and gp37/40, respectively, were found to interfere with peptide presentation at different steps in the major histocompatibility complex (MHC) class I pathway of antigen processing and presentation in fibroblasts. Accordingly, they were proposed to prevent recognition and lysis of infected fibroblasts by cytolytic T lymphocytes (CTL) during the E phase of viral gene expression. We document here that the previously identified MHC class I Dd-restricted antigenic peptide257AGPPRYSRI265encoded by genem164is processed as well as presented for recognition by m164-specific CTL during the E and late phases of viral ...
The Journal of general virology, 2001
Liver and intestinal epithelial cells are a major target of infection by cytomegaloviruses (CMV), causing severe disease in affected organs of immunocompromised patients. CMV downregulates major histocompatibility complex class I (MHC-I) molecule expression in fibroblasts in order to avoid lysis by CD8(+) cytotoxic T lymphocytes. However, MHC-I expression in human cytomegalovirus (HCMV)-infected hepatic tissue was reported to be increased. As it is unclear at present whether HCMV affects MHC-I expression in epithelial cells, new cell culture models for HCMV infection of differentiated hepatobiliary cell lines were established. HCMV immediate early gene expression was achieved in 60 to 95% of cells. Progression of the HCMV replication cycle differed from prototypic infection of fibroblasts, since structural early and late proteins were produced at low levels and HCMV progeny yielded much lower titres in hepatobiliary cells. In contrast, HCMV glycoproteins, gpUS2, gpUS3, gpUS6 and gpU...