Th17 lymphocytes in respiratory syncytial virus infection

Abstract

Infection by respiratory syncytial virus (RSV) affects approximately 33 million infants annually worldwide and is a major cause of hospitalizations. Helper T lymphocytes (Th) play a central role in the immune response during such infections. However, Th lymphocytes that produce interleukin 17 (IL-17), known as Th17 lymphocytes, in addition to been protective can also cause pathology that accompany this type of infection. The protective effects of Th17 is associated with better prognosis in most infected individuals but heightened Th17 responses causes inflammation and pathology in others. Studies employing animal models haves shown that activated Th17 lymphocytes recruit neutrophils and facilitate tertiary lymphoid structure development in infected lungs. However, IL-17 also inhibits the ability of CD8+ lymphocytes to clear viral particles and acts synergistically with the innate immune system to exacerbate inflammation. Furthermore, IL-17 enhances IL-13 production which, in turn, promotes the activation of Th2 lymphocytes and excessive mucus production. Studies of these animal models have also shown that a lack of, or inadequate, responses by the Th1 subset of T lymphocytes enhances Th17-mediated responses and that this is detrimental during RSV co-infection in experimental asthma. The available evidence, therefore, indicates that Th17 can play contradictory roles during RSV infections. The factors that determine the shift in the balance between beneficial and adverse Th17 mediated effects during RSV infection remains to be determined.

Figure 1

IL-17 mediated responses in the respiratory tract during RSV infections. RSV virus particles infect ciliated epithelial cells in the lower respiratory tract. C3a and other mediators of inflammation are then released from epithelial cells in response to the infection and this, in turn, induces IL-17 production (dark blue colour). During the early phase of the response to RSV infection, IL-17 is produced by CD11b⁺ innate immune cells. Subsequently, the production of IL-17 is predominantly by CD4⁺ Th17 lymphocytes. The production of IL-17 initiates a number of effects in the respiratory tract. Thus, IL-17 induces mild inflammation and exacerbates inflammatory responses triggered by other signals and cytokines. In this scenario, single stranded RNA in RSV particles bind to TLR3 and synergize with IL-17 to induce IL-6 (orange colour) and IL-8 (blue colour) by fibroblasts (Fc). The binding of double stranded RNA to TLR7, however, is inhibitory to IL-17-mediated responses and, instead, promotes Th1-mediated responses. IL-17 co-operates with IL-1β and TNFα to induce the release of chemokines that mediate neutrophil recruitment. Furthermore, IL-17 induces mucus production from epithelial cells. IL-17 also binds receptors on CD8⁺ T lymphocytes and inhibits their ability to reduce viral load. Cytokines produced by Th1 and Th2 lymphocytes, IFNγ and IL-13, in contrast, inhibit IL-17 production [25,33].