Characterization of the cross reactive T cell repertoire in the context of heterosubtypic influenza A virus infection

Abstract

Abstract Influenza A viruses (IAVs) are a major respiratory pathogen with the capacity to rapidly mutate and escape an individual’s existing immunity to a specific strain generated by vaccination or naturally acquired infection. CD8 T cells however, target conserved proteins that could be shared across multiple subtypes. Heterosubtypic immunity to IAVs, where memory T cells generated to a previous IAV are reactivated during re-challenge with an antigenically distinct virus, may be important in generating an effective immune response to different and/or novel strains of IAV. Specifically, cross reactive T cells, where a T cell receptor (TCR) can recognize more than one epitope displayed on an MHC-I molecule, could facilitate rapid recognition of conserved or nominally divergent epitopes, may have the potential to alter the TCR repertoire over the course of heterosubtypic infections, and might be selected for by the immune system. Utilizing 8 variant influenza viruses for priming and secondary challenge, our preliminary data has shown that cross reactive TCRs seen in primary infection with one IAV can mount a robust and effective memory response to a different IAV, even if the epitope has slightly mutated. However, selection for cross reactive receptors may create a narrowed repertoire consisting of a few clonotypes over the course of many repeated heterosubtypic IAV infections, covering a narrow range of antigenic space representing the mutant epitopes encountered. Paradoxically, this selection for cross-reactivity may provide a substantial escape opportunity with future antigenic variations. Ongoing work focuses on how repeated IAV challenges shape and are shaped by these selected cross-reactive T cell pools.