Mouse Models of Heterologous Flavivirus Immunity: A Role for Cross-Reactive T Cells

Abstract

Most of the world is at risk of being infected with a flavivirus such as dengue virus, West Nile virus, yellow fever virus, Japanese encephalitis virus, tick-borne encephalitis virus, and Zika virus, significantly impacting millions of lives. Importantly, many of these genetically similar viruses co-circulate within the same geographic regions, making it likely for individuals living in areas of high flavivirus endemicity to be infected with multiple flaviviruses during their lifetime. Following a flavivirus infection, a robust virus-specific T cell response is generated and the memory recall of this response has been demonstrated to provide long-lasting immunity, protecting against reinfection with the same pathogen. However, multiple studies have shown that this flavivirus specific T cell response can be cross-reactive and active during heterologous flavivirus infection, leading to the question: How does immunity to one flavivirus shape immunity to the next, and how does this impact disease? It has been proposed that in some cases unfavorable disease outcomes may be caused by lower avidity cross-reactive memory T cells generated during a primary flavivirus infection that preferentially expand during a secondary heterologous infection and function sub optimally against the new pathogen. While in other cases, these cross-reactive cells still have the potential to facilitate cross-protection. In this review, we focus on cross-reactive T cell responses to flaviviruses and the concepts and consequences of T cell cross-reactivity, with particular emphasis linking data generated using murine models to our new understanding of disease outcomes following heterologous flavivirus infection.

Keywords: T cell cross-reactivity; Zika; dengue; flavivirus; heterologous immunity; original antigenic sin.

Figure 1

Flavivirus genome and proteins. The flavivirus genome consists of a single positive-stranded RNA molecule with a 5′ methylguanosine cap followed by an untranslated region (UTR), open reading frame (ORF) and a 3′ UTR with multiple variable stem loop structures. The genome is translated from a single ORF into a polyprotein that is proteolytically cleaved by both viral and host proteases. The genome codes for three structural proteins (capsid, membrane, and envelope) and seven non-structural proteins (NS1, NS2a, NS2b, NS3, NS4a, NS4b, and NS5). Theoretically, peptides of any of these structural or non-structural proteins have the potential to be targets of the virus-specific T cell response. Multiple flavivirus cross-reactive T cell epitopes with murine MHC restriction have been demonstrated in various murine models, the breadth of which are indicated by the triangles below the polyprotein. For detailed information on these identified cross-reactive epitopes see Table 2.

Figure 2

Consequences of T cell cross-reactivity during heterologous infection. During a primary infection, (for example with Virus B), a diverse T cell response may be generated against multiple Virus-B-specific epitopes (Red) possibly in addition to some cross-reactive epitopes (Purple); both of which will contract to some degree following viral clearance. However, if an infection with Virus B is preceded by Virus A, and the two viruses share responses to the same cross-reactive epitopes, an altered T cell immunodominance hierarchy may occur during the heterologous infection. In this case, at the point of infection with Virus B, cross-reactive memory T cells generated during infection with Virus A are already present at a higher frequency and lower activation threshold than naïve T cells specific for Virus A. This can lead to a preferential expansion of the cross-reactive T cells often at the expense of the virus specific ones, or “immunodomination.” During this process, memory cells specific to Virus A can even be lost from memory attrition, potentially impacting protection from future infections with Virus A. Sometimes, T cell cross-reactivity can occur in the absence of neutralizing antibody cross-reactivity, resulting in higher antigen loads than what would normally be present in a homologous boosted infection (Virus B followed by Virus B) which can lead to profound T cell activation of a higher magnitude. In the case of some flaviviruses cross-reactive antibody can even increase antigen load via ADE. The preferentially expanded, cross-reactive T cells can display different avidity compared to those that would have been generated during an infection with Virus A in the absence of prior heterologous exposure. During a primary infection with Virus A, the cross-reactive population would normally have a stronger avidity to the peptide variant of Virus A. However, during a heterologous infection, they have a stronger avidity to the peptide variant of the prior infection, Virus B. T cell cross-reactivity during heterologous infection can even have functional implications for cross-reactive T cells, though the alterations to cytokine profiles and their consequences is often virus-specific. All of these alterations to T cell populations and their functional capacities will dictate the balance between cross-protection and immunopathology, and can even result in viral escape; The sum of these, ultimately defining the disease outcome.