Influenza matrix 1‐specific human CD4+FOXP3+ and FOXP3− regulatory T cells can be detected long after viral clearance

Control and termination of infection with Influenza A virus is associated with increased IL‐10 production in mouse models. Notably, IL‐10 can be produced by Treg. Therefore, we investigated whether the population of IL‐10‐producing influenza‐specific CD4⁺ T cells comprised Treg as they are potent suppressors of the adaptive immune response. Influenza‐specific IL‐10‐producing T cells were detected in all human donors displaying influenza‐specific immunity. Isolation of Matrix 1 protein‐specific IL‐10‐producing T‐cell clones revealed that a substantial proportion of these T‐cell clones displayed the capacity to suppress effector cells, functionally identifying them as Treg. Both FOXP3⁺ and FOXP3^? CD4⁺ Treg were isolated and all were able to exert their suppressive capacity when stimulated with cognate antigen, including influenza virus‐infected cells. In vitro suppression was not mediated by IL‐10 but involved interference with the IL‐2 axis. The isolated Treg suppressed amongst others the IL‐2 production of influenza‐specific T‐helper cells as well as partially prevented the upregulation of the high‐affinity IL‐2 receptor on CD8 effector cells. So far the induction of virus‐specific Treg has only been studied in the context of chronic viral infections. This study demonstrates that virus‐specific Treg can also be induced by viruses that are rapidly cleared in humans.