Influenza A virus (IAV) infection in humans leads to expansion of highly diverse CD8 T cell repertoires cross-reactive with Epstein Barr virus (EBV)

Abstract

Abstract The competence of T cell responses predominantly depends on how efficient T cell receptors (TCRs) are at recognizing antigenic epitopes. We show here that during acute severely symptomatic IAV infection there was an expansion of IAV-M1/EBV-BRLF1 and IAV-M1/EBV-BMLF1 double-tetramer+ cells directly ex vivo in 5 HLA-A2+ patients. We questioned whether this expansion specific to these two different cross-reactive responses would lead to alterations in the IAV-M158, EBV-BRLF1109 and -BMLF1280 TCR repertoires from before and during acute IAV infection. Using staining with VB mAb we found that T cell responses generated to these epitopes became surprisingly more polyclonal, with the sharing of Vb between M1, BMLF1 and BRLF1 populations which is not seen in healthy donor. Furthermore, by using next generation sequencing and single-cell analysis of TCRα and TCRβ repertoire of tetramer sorted IAV-M1 cells we showed dramatic changes in specific clonotype usage during acute IAV infection compared to before infection. In summary, these changes in TCR repertoire during acute symptomatic IAV infection suggest that during severe infection there is a preferential expansion of highly diverse cross-reactive responses between IAV and the persistent virus, EBV, which leads to permanent changes in TCR repertoires to both of these two viruses (NIH AI049320 and NIH AI109858).