Cross-priming induces immunodomination in the presence of viral MHC class I inhibition

• Published in: PLoS pathogens Vol. 14; no. 2; p. e1006883
• Main Authors: Lauron, Elvin J, Yang, Liping, Elliott, Jabari I, Gainey, Maria D, Fremont, Daved H, Yokoyama, Wayne M
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 01.02.2018; Public Library of Science (PLoS)
• Subjects: Animals; Antigen presentation; Antigenic determinants; Antigens, Viral - immunology; Antigens, Viral - metabolism; Artificial chromosomes; Biology and Life Sciences; CD8 antigen; Cells, Cultured; Cercopithecus aethiops; Clonal deletion; Cowpox; Cross-Priming - immunology; Cytotoxicity; Epitopes; Epitopes, T-Lymphocyte - immunology; Epitopes, T-Lymphocyte - metabolism; Funding; Health aspects; HeLa Cells; Histocompatibility antigen H-2; Histocompatibility Antigens Class I - immunology; Humans; Immune response; Immunity; Immunodominance; Immunodominant Epitopes - metabolism; Immunology; Infections; Inhibition; Inhibitors; Lymphocytes; Lymphocytes T; Major histocompatibility complex; Medicine; Medicine and Health Sciences; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Transgenic; Peptides; Physiological aspects; Poxviruses; Priming; Research and Analysis Methods; Smallpox; T cell receptors; T-Lymphocytes, Cytotoxic - immunology; Tuberculosis; Vaccines; Vero Cells; Viral infections; Viral research; Viruses; United States > US; Missouri
• ISSN: 1553-7374; 1553-7366; 1553-7374
• DOI: 10.1371/journal.ppat.1006883

Viruses have evolved mechanisms of MHCI inhibition in order to evade recognition by cytotoxic CD8+ T cells (CTLs), which is well-illustrated by our prior studies on cowpox virus (CPXV) that encodes potent MHCI inhibitors. Deletion of CPXV viral MHCI inhibitors markedly attenuated in vivo infection due to effects on CTL effector function, not priming. However, the CTL response to CPXV in C57BL/6 mice is dominated by a single peptide antigen presented by H-2Kb. Here we evaluated the effect of viral MHCI inhibition on immunodominant (IDE) and subdominant epitopes (SDE) as this has not been thoroughly examined. We found that cross-priming, but not cross-dressing, is the main mechanism driving IDE and SDE CTL responses following CPXV infection. Secretion of the immunodominant antigen was not required for immunodominance. Instead, immunodominance was caused by CTL interference, known as immunodomination. Both immunodomination and cross-priming of SDEs were not affected by MHCI inhibition. SDE-specific CTLs were also capable of exerting immunodomination during primary and secondary responses, which was in part dependent on antigen abundance. Furthermore, CTL responses directed solely against SDEs protected against lethal CPXV infection, but only in the absence of the CPXV MHCI inhibitors. Thus, both SDE and IDE responses can contribute to protective immunity against poxviruses, implying that these principles apply to poxvirus-based vaccines.