LAG-3 expressing antigen-specific CD4+ T cells attenuate lung inflammation during acute influenza virus infection

The host immune system responds to influenza virus infection for eradication of the virus but the immune response associated inflammation causes tissue injury and damage to the host as well. In our antigen-specific mouse model system for influenza virus infection, influenza hemagglutinin antigen-specific CD4+ T cells responded to acute infection with Th1 effector phenotype. A significant proportion of them were also with concurrent expression of LAG-3, CTLA-4, GITR or CD25. Adoptive transfer of purified LAG-3 expressing hemagglutinin antigen-specific CD4+ T cells controlled lung inflammation with acute influenza virus infection, as represented by the activation of co-transferred influenza hemagglutinin antigen-specific CD8+ T cells. Control of the inflammation by LAG-3 expressing antigen-specific Th1 CD4+ T cells was not necessarily associated with impaired capacity of virus eradication. These results reveal, besides effector function for virus eradication, subsets of CD4+ T cells activated by acute influenza virus infection also acquired regulatory function to attenuate inflammation for reducing the damage to the host. These subsets of CD4+ T cells may be employed as the practical handle for management of severe influenza disease.