Abstract
Smallpox and monkeypox pose severe threats to human health. Other orthopoxviruses are comparably virulent in their natural hosts, including ectromelia, the cause of mousepox. Disease severity is linked to an array of immunomodulatory proteins including the B22 family, which has homologs in all pathogenic orthopoxviruses but not attenuated vaccine strains. We demonstrate that the ectromelia B22 member, C15, is necessary and sufficient for selective inhibition of CD4+ but not CD8+ T cell activation by immunogenic peptide and superantigen. Inhibition is achieved not by down-regulation of surface MHC- II or co-stimulatory protein surface expression but rather by interference with antigen presentation. The appreciable outcome is interference with CD4+ T cell synapse formation as determined by imaging studies and lipid raft disruption. Consequently, CD4+ T cell activating stimulus shifts to uninfected antigen-presenting cells that have received antigen from infected cells. This work provides insight into the immunomodulatory strategies of orthopoxviruses by elucidating a mechanism for specific targeting of CD4+ T cell activation, reflecting the importance of this cell type in control of the virus.
Highlights
CD4+ T cells are a critical adaptive immune cell type with roles in B cell and CD8+ T cell help, inflammatory cytokine secretion and, in some cases, direct cytolytic function
We show here that the C15 protein of ectromelia, the cause of mousepox, inhibits CD4+ T cell activation through a novel immunoevasion mechanism that results in disruption of synapse formation
The observed inhibitory effect suggests that Major Histocompatibility Complex class II (MHCII) processing and presentation of ECTV antigens relies on indirect presentation of antigen by an uninfected antigen-presenting cell (APC) rather than direct presentation
Summary
CD4+ T cells are a critical adaptive immune cell type with roles in B cell and CD8+ T cell help, inflammatory cytokine secretion and, in some cases, direct cytolytic function. The critical initiating events for CD4+ T cell activation are Major Histocompatibility Complex class II (MHCII) presentation of pathogen derived peptides (epitopes) in combination with co-stimulatory signals through CD28 [1]. As CD4+ T cells play important roles in clearing many viral infections, several mechanisms by which viruses inhibit MHCII antigen processing and presentation have been described [2]. Most steps of the MHCII maturation process are targeted, from inhibition of the master transcription factor CIITA [3,4,5,6,7,8] to interference with complex formation and trafficking [9,10,11], as well as forced degradation of mature MHCII molecules [12, 13]. Hepatitis C Virus inhibits the function of endosomal proteases required for generating some MHCII binding peptides [14]. Though discrete mechanisms of inhibition have been described, there are relatively few examples of CD4+ T cell inhibition in the literature compared to the many of viral inhibition of MHCI presentation to CD8+ T cells, perhaps reflecting historical inattention to the role of CD4+ T cells in viral clearance
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
