Del Val, Margarita; Hengel, Hartmut; Häcker, Hans; Hartlaub, Udo; Ruppert, Thomas; Lucin, Pero; Koszinowski, Ulrich H.
Cytomegalovirus prevents antigen presentation by blocking the transport of peptide-loaded major histocompatibility complex class I molecules into the medial-Golgi compartment.
In: The journal of experimental medicine, Vol. 176: S. 729-738
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 (del Val, M., H.-J. Schlicht,
T. Ruppert, M. J. Reddehase, and 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.