MAVS Deficiency Is Associated With a Reduced T Cell Response Upon Secondary RSV Infection in Mice

Abstract

Infections with respiratory syncytial virus (RSV) occurs repeatedly throughout life because sustained, protective memory responses fail to develop. Why this occurs is not known. During RSV infection the recognition of the virus via the cytosolic RIG-I like receptors and signaling via the adaptor protein MAVS is crucial for mounting an innate immune response. However, if this signaling pathway is important for T cell responses during primary infection and during re-infection is not fully elucidated. We describe a second peak of pro-inflammatory mediators during the primary immune response to RSV that coincides with the arrival of T cells into the lung. This second peak of cytokines/chemokines is regulated differently than the early peak and is largely independent of signaling via MAVS. This was concurrent with Mavs −/− mice mounting a strong T cell response to primary RSV infection, with robust IFN-γ; and Granzyme B production. However, after RSV re-infection, Mavs −/− mice showed fewer CD4 + and CD8 + short term memory T cells and their capacity to produce IFN-γ; and Granzyme B, was decreased. In sum, cytosolic recognition of RSV is important not only for initiating innate anti-viral responses but also for generating or maintaining efficient, short term T cell memory responses.

Type I interferons and MAVS signaling are necessary for tissue resident memory CD8+ T cell responses to RSV infection

“…One day after re-infection, neutrophil numbers peaked in the airways and lung tissue while alveolar macrophage (AM) numbers remained overall unchanged during the re-infection period (S2A-S2C Fig) . These responses are very similar to what is observed during primary infection [32,33] but to a much lower magnitude. Naïve CD4 + and CD8 + T cell numbers in the lung remained constant, yet as expected, total CD8 + and CD4 + T cell numbers increased during re-infection (S2D-S2G Fig) . The numbers of total CD4 + and CD8 + T cells at day 4 post re-infection were comparable to numbers recorded at the peak of the primary infection (day 7-8) in this model [32,39,40]. The increase was driven mainly by an expansion in the number (g) Stacked analysis of the subpopulations of CD8 + T EF cells bases on expression of CD103 and/or CD69.…”

“…During RSV re-infection, despite major differences in T RM cell numbers and function in wt mice compared with Mavs -/-, we found no differences in viral load at day 2 post re-infection although, in these experiments, wt mice showed slightly faster viral clearance than Mavs -/mice at day 4 post re-infection. However, low viral load may contribute to some experimental variability as we had previously found no difference in viral load day 4 post re-infection [39]. Arguing for a role of T RM cell in RSV control, other groups have shown that, in the absence of antibodies, adoptive transfer of airway CD8 + T cells is enough to control disease development [18].…”

“…We and others have reported that during the adaptive phase of the immune response against primary RSV infection, Mavs -/mice are able to elicit RSVspecific CD4 + and CD8 + T cell responses comparable to those in wt mice [32,34,39]. However, Mavs -/mice exhibit an impaired memory response to RSV, displaying reduced numbers of RSV-specific CD8 + T cells [39]. Whether type I IFNs, MAVS and MyD88/TRIF signaling also impact T RM cell responses in the lung has not been previously addressed.…”

“…However, type I IFNs also play a role in T cell differentiation and memory program acquisition [37] and T cells cultured ex vivo in the presence of type I IFNs upregulate residency-associated markers [38]. We and others have reported that during the adaptive phase of the immune response against primary RSV infection, Mavs -/mice are able to elicit RSVspecific CD4 + and CD8 + T cell responses comparable to those in wt mice [32,34,39]. However, Mavs -/mice exhibit an impaired memory response to RSV, displaying reduced numbers of RSV-specific CD8 + T cells [39].…”

“…Our results show that RSV infection results in the generation of lung CD8 + T RM cells, which expand after secondary challenge. The direct effect of T RM cells on clearing RSV is difficult to assess in the mouse model as, in contrast to humans, mice are capable of producing and maintaining RSV-specific antibody responses to rapidly inhibit infection [39]. As a consequence, viral load at the peak of RSV re-infection is 1000-fold lower than in primary infection [32].…”