T cell programming by the cytomegalovirus MHC class I homologue UL18

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Abstract Rhesus cytomegalovirus (RhCMV) strain 68-1 vectored vaccines elicit MHC-II-and MHC-E-, but not classical, MHC-Ia-restricted CD8+ T cell responses. This is due to the presence of a viral MHC-E ligand encoded by Rh67 (UL40 in HCMV) and the combined deletion or inactivation of Rh157.5/.4 (UL128/UL130 in HCMV) and Rh158–Rh161 (members of the UL146 family of CXC chemokines). Importantly, the ability to elicit MHC-E-restricted CD8+ T cell responses correlates with the efficacy of RhCMV-vectored vaccines to control and clear infection by highly virulent simian immunodeficiency virus (SIV). To investigate whether HCMV encodes additional modulators of unconventional CD8+ T-cell priming that are not conserved in non-human primate CMVs, we inserted non-conserved HCMV genes into 68-1 and monitored the induction of the unconventional CD8+ T cells. This screen revealed that the UL18 protein of HCMV prevented the induction of MHC-II and MHC-E restricted CD8+ T cells resulting in a classical, MHC-Ia-targeted T cell response. UL18 is a MHC-Ia homolog and associates with cellular β2 microglobulin and peptides. However, unlike host MHC-Ia, this trimeric complex does not engage with the T cell receptor, but binds with high affinity to the inhibitory receptor LIR-1 widely expressed on leukocytes. Indeed, 68-1 recombinants expressing UL18 mutants lacking LIR-1-binding no longer interfered with the induction of MHC-II and MHC-E restricted CD8+ T cells. Thus, HCMV UL18 appears to prevent unconventional T cell priming by binding to LIR-1. In the event that this mechanism is conserved in the human host, UL18 could interfere with HCMV/HIV vaccine efficacy as the ability to elicit MHC-E-restricted CD8+ T cells is likely required for protection against HIV.

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