Abstract
Infections by human CMV are controlled by cellular immune responses. Professional APC such as monocytes and macrophages can be infected in vivo and are considered as a reservoir of virus. However, CMV-specific CD4(+) responses against infected APC have not been reported. To develop a model of CD4-infected APC interaction, we have transfected the U373MG astrocytoma cell line with the class II transactivator (CIITA). Confocal microscopy experiments showed that U373MG-CIITA cells expressed markers characteristic of APC. Functional assays demonstrated that infected U373MG-CIITA APC processed and presented both exogenous and endogenously neosynthesized nuclear immediate early (IE) protein 1 through the MHC class II pathway. More importantly, endogenous presentation of IE1 by infected APC lead to efficient control of CMV infection as revealed by decreased viral titer. Thus, these results describe the endogenous presentation of a nuclear viral protein by the MHC class II pathway and suggest that IE1-specific CD4(+) T cells may play an important role in CMV infection by directly acting against infected APC.
Highlights
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We found that IE1-specific CD4ϩ T cells were efficiently activated by infected U373MG-class II transactivator (CIITA) cells through endogenous presentation
In the present study, that IE1-specific CD4ϩ T cells recognize IE1 endogenously produced by the infected APC and that this recognition results in the control of infection in vitro
Summary
IE, immediate early; gB, glycoprotein B; pp, phosphoprotein; MHC-II, MHC class II; CIITA, MHC-II transactivator; Tb, tuberprotein 1, IE2, glycoprotein B (gB), and phosphoprotein (pp) 65, either at the population (16 –18) or the clonal [19, 20] level. Because analysis of presentation and consequences of recognition of infected APC by CMV-specific CD4ϩ T cells have not yet been investigated, we have stably transfected permissive U373MG astrocytoma cells with the cDNA encoding for the MHC class II (MHC-II) transactivator (CIITA) to construct a cell model of Ag presentation [31]. We used the model of U373MG-CIITA cells to investigate the recognition of infected APCs by IE1-specific CD4ϩ T cell clones and the effect on CMV infection. We found that IE1-specific CD4ϩ T cells were efficiently activated by infected U373MG-CIITA cells through endogenous presentation. This activation resulted in IFN-␥ production by and proliferation of IE1specific CD4ϩ T cell clones. We conclude that recognition of infected APCs can be performed by IE1-specific CD4ϩ T cells and that this interaction may be of importance in the control of CMV infections in vivo
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