1. Human cytomegalovirus UL18 prevents priming of MHC-E- and MHC-II-restricted CD8 + T cells.
- Author
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Malouli D, Taher H, Mansouri M, Iyer RF, Reed J, Papen C, Schell JB, Beechwood T, Martinson T, Morrow D, Hughes CM, Gilbride RM, Randall K, Ford JC, Belica K, Ojha S, Sacha JB, Bimber BN, Hansen SG, Picker LJ, and Früh K
- Subjects
- Animals, Humans, Viral Proteins immunology, Histocompatibility Antigens Class II immunology, Histocompatibility Antigens Class I immunology, Cytomegalovirus Infections immunology, Cytomegalovirus Infections prevention & control, CD8-Positive T-Lymphocytes immunology, Cytomegalovirus immunology, Macaca mulatta
- Abstract
Rhesus cytomegalovirus (RhCMV) vectors elicit major histocompatibility complex (MHC)-E-restricted CD8
+ T cells that stringently control simian immunodeficiency virus (SIV) in rhesus macaques. These responses require deletion of eight RhCMV chemokine-like open reading frames (ORFs) that are conserved in human cytomegalovirus (HCMV). To determine whether HCMV encodes additional, nonconserved inhibitors of unconventional T cell priming, we inserted 41 HCMV-specific ORFs into a chemokine-deficient strain (68-1 RhCMV). Monitoring of epitope recognition revealed that HCMV UL18 prevented unconventional T cell priming, resulting in MHC-Ia-targeted responses. UL18 is homologous to MHC-I but does not engage T cell receptors and, instead, binds with high affinity to inhibitory leukocyte immunoglobulin-like receptor-1 (LIR-1). UL18 lacking LIR-1 binding no longer interfered with MHC-E-restricted T cell stimulation by RhCMV-infected cells or the induction of unconventionally restricted T cells. Thus, LIR-1 binding needs to be deleted from UL18 of HCMV/HIV vaccines to allow for the induction of protective MHC-E-restricted T cells.- Published
- 2024
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