Human cytomegalovirus UL18 prevents priming of MHC-E– and MHC-II–restricted CD8 <sup>+</sup> T cells
Rhesus cytomegalovirus (RhCMV) vectors elicit major histocompatibility complex (MHC)-E-restricted CD8<sup>+</sup> 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.
Authors
- David Morrow (ORCID: https://orcid.org/0000-0003-4686-830X)
- Jason S. Reed
- Karina Belica (ORCID: https://orcid.org/0009-0001-5925-3657)
- Colette M. Hughes
- Jonah B. Sacha (ORCID: https://orcid.org/0000-0002-7633-3122)
- Teresa Beechwood (ORCID: https://orcid.org/0009-0008-8493-6071)
- Thomas Martinson
- Scott G. Hansen (ORCID: https://orcid.org/0000-0002-9845-6481)
- Roxanne M. Gilbride (ORCID: https://orcid.org/0000-0001-6040-104X)
- Courtney R. Papen
- Husam Taher
- Benjamin N. Bimber (ORCID: https://orcid.org/0000-0001-8092-3080)
- Ravi Iyer (ORCID: https://orcid.org/0000-0003-2249-266X)
- Julia C. Ford (ORCID: https://orcid.org/0000-0002-4989-2842)
- John B. Schell (ORCID: https://orcid.org/0000-0001-6707-7051)
- Kurt T. Randall (ORCID: https://orcid.org/0009-0005-7553-3893)
- Louis J. Picker (ORCID: https://orcid.org/0000-0003-0546-398X)
- Daniel Malouli (ORCID: https://orcid.org/0000-0003-1287-7283)
- Mandana Mansouri (ORCID: https://orcid.org/0000-0003-1299-0817)
- Sohita Ojha (ORCID: https://orcid.org/0009-0008-4473-7078)
- Klaus Früh
Institutions
- Oregon National Primate Research Center (US)
Publication Details
- Journal
- Science Immunology
- Published
- 2024-10-11
- DOI
- https://doi.org/10.1126/sciimmunol.adp5216
- Citations
- 9
- Primary Topic
- Cytomegalovirus and herpesvirus research
- Type
- article
- Field-Weighted Citation Impact
- 3.48
Funders
- National Institutes of Health
- Oregon National Primate Research Center
- National Institute of Allergy and Infectious Diseases