A crucial role for IL-21 in controlling CD4 T cell responses to respiratory viral infection

Abstract

Respiratory syncytial virus (RSV) is a pneumovirus that infects almost all children by the age of three, and causes an intense pulmonary infiltrate termed bronchiolitis. The tissue damage caused by this immune response significantly reduces lung function such that hospitalisation and mechanical ventilation may be required. There is no licensed vaccine against RSV, partly because the exact immunological mechanism responsible for bronchiolitis remains unclear, though CD4 and CD8 T cells are known to be essential. Interleukin-21 (IL-21) is a recently identified member of the γc chain cytokine family, important in autoimmunity, cancer, and chronic viral infections. Produced mainly by CD4 T cells, IL-21 affects the responses of several cell types but is particularly important for enhancing activation and survival of CD8 T cells. As such, it was hypothesised that IL-21 could be targeted therapeutically to reduce anti-RSV CD8 T cell responses and reduce the incidence of bronchiolitis. This hypothesis was tested in three models of RSV disease. Here, it is shown that IL-21 is critical for control of CD4 T cell responses rather than CD8. IL-21 depletion increases T cell responses, including cell recruitment and cytokine production, thereby increasing disease. Conversely, it reduced regulatory T cell influx and antibody production. In contrast, IL-21 over-expression ablates the anti-viral T cell response and RSV disease without affecting regulatory T cells. Also, early chemokine production by infected epithelial cells is inhibited and that DC migration is affected, possibly reducing T cell activation and influx. Antibody 4 production is also reduced, and consequently lymphocyte memory development is blocked resulting in no protection against viral rechallenge. Therefore, IL-21 plays a crucial role in the development of anti-viral pulmonary immunity and should be considered as part of a therapy to alleviate primary RSV disease in conjunction with other factors to boost anti-viral memory.