Non-canonical clonal expansion of autoreactive CD8⁺ T cells following influenza infection

T cell receptors (TCRs) are inherently polyreactive. A vast repertoire of polyreactive TCRs not only ensure a response to essentially all possible microbial antigen but also underlies the host susceptibility to autoimmunity, which may be triggered or precipitated by microbial infections. Here we report that influenza A virus (IAV) infection in mice triggers robust expansion of naïve OT-I CD8⁺ T cells, which do not recognize IAV antigen but cryptic self antigen. This expansion was dependent on class I MHC, reaching a magnitude comparable to that of T cells reacting to cognate viral antigen. This massive OT-I expansion was nonetheless abortive, owing to precipitous cell death and suppression by regulatory T cells. This non-canonical CD8⁺ T cell response to viral infection, presumably driven by cryptic self antigen co-stimulated by the inflammation and tissue damage, highlights a potentially common mechanism underlying the risk of developing autoimmunity following viral infection.