Uncovering the interplay between CD8, CD4 and antibody responses to complex pathogens

Abstract

Vaccinia virus (VACV) was used as the vaccine strain to eradicate smallpox. VACV is still administered to healthcare workers or researchers who are at risk of contracting the virus, and to military personnel. Thus, VACV represents a weapon against outbreaks, both natural (e.g., monkeypox) or man-made (bioterror). This virus is also used as a vector for experimental vaccine development (cancer/infectious disease). As a prototypic poxvirus, VACV is a model system for studying host-pathogen interactions. Until recently, little was known about the targets of host immune responses, which was likely owing to VACVs large genome (>200 open reading frames). However, the last few years have witnessed an explosion of data, and VACV has quickly become a useful model to study adaptive immune responses. This review summarizes and highlights key findings based on identification of VACV antigens targeted by the immune system (CD4, CD8 and antibodies) and the complex interplay between responses.

Figure 1. Kinetic and functional categories of vaccinia virus antigens either contained within vaccinia virus genome and virion or targeted by adaptive immunity: CD8 and CD4/antibody target different sets of viral antigens

Left panels show the distribution of vaccinia virus (VACV) proteins within the viral genome (grey; total of 211 unique VACV genes) and top 21 (10% of all open reading frames) most abundant proteins contained within virion (black) based on (A) expression kinetics (IE, E, E/L, L, unknown) or (B) functional category (virulence, regulation, structural, unknown). Right panels show the distribution of VACV proteins identified as targets of CD8 T cells (black; top 23 most prevalent antigens), CD4 T cells (grey; top 21 antigens, >40% of tested donors) or antibodies (white; top 19 antigens, >20% of tested donors) based on (A) expression kinetics (IE, E, E/L, L, unknown) or (B) functional category0 (virulence, regulation, structural, unknown). Ab: Antibody; E: Early; E/L: Early/late; IE: Immediate-early; L: Late. Data were compiled from published literature based on experimental data as described in the text.

Figure 2. Vaccinia virus mRNA early expression pattern correlates with CD8 T-cell responses, whereas late expression correlates with CD4 and antibody responses

The MER was calculated by taking the average of individual mRNA rankings of each open reading frame at 4 h and 24 h postinfection based on [9]. Low MER numbers correspond to high expression levels. Similar analysis was performed with median ranking of protein abundance in the virion based on studies by Chung et al. [31] and Resch et al. [32]. (A) MER of the 23 most prevalently (black), nonprevalent (grey) or nonantigenic (nonrecognized; white) recognized ORFs by CD8 T cells of mRNA levels at 4 h and 24 h and protein abundance in virion. (B) MER of the top 21 (black), remaining antigenic (grey) or nonantigenic (nonrecognized; white) recognized ORFs by CD4 T cells of mRNA levels at 4 h and 24 h and protein abundance in virion. (C) MER of the top 19 (black), remaining antigenic (grey) or nonantigenic (non-recognized; white) recognized ORFs by antibodies of mRNA levels at 4 h and 24 h and protein abundance in virion. Ab: Antibody; MER: Median mRNA expression ranking.