IL-4Rα on CD4+ T cells plays a pathogenic role in respiratory syncytial virus reinfection in mice infected initially as neonates

Abstract

RSV is the major cause of severe bronchiolitis in infants, and severe bronchiolitis as a result of RSV is associated with subsequent asthma development. A biased Th2 immune response is thought to be responsible for neonatal RSV pathogenesis; however, molecular mechanisms remain elusive. Our data demonstrate, for the first time, that IL-4Rα is up-regulated in vitro on human CD4(+) T cells from cord blood following RSV stimulation and in vivo on mouse pulmonary CD4(+) T cells upon reinfection of mice, initially infected as neonates. Th cell-specific deletion of Il4ra attenuated Th2 responses and abolished the immunopathophysiology upon reinfection, including airway hyper-reactivity, eosinophilia, and mucus hyperproduction in mice infected initially as neonates. These findings support a pathogenic role for IL-4Rα on Th cells following RSV reinfection of mice initially infected as neonates; more importantly, our data from human cells suggest that the same mechanism occurs in humans.

Aberrant T cell immunity triggered by human Respiratory Syncytial Virus and human Metapneumovirus infection

“…gene in CD4 C T cells abolished hRSV-induced airway AHR and lung damage upon reinfection with hRSV. 87 However, these results are controversial because several reports have shown that CD4 C T cells are required for the clearance of the virus and to promote antibody response against hRSV. 60,[88][89][90] In this sense, it seems that dysregulation of CD4 C T cells promote harmful Th profiles but these cells are still required for hRSV clearance.…”

“…86 The pathogenic role of CD4 C T during re-infection with hRSV in adult mice, after being infected as neonates, can be explained by the induction of an exaggerated T H 2 response, demonstrated by the cytokine profile observed in these animals. 87 This could be explained, at least in part, by the upregulation of the IL-4Ra. Specific deletion of the IL-4Ra.…”

Limited Type I Interferons and Plasmacytoid Dendritic Cells during Neonatal Respiratory Syncytial Virus Infection Permit Immunopathogenesis upon Reinfection

“…Using this model, we have recently demonstrated that interleukin 4 receptor ␣ (IL-4R␣) on Th cells plays a pathogenic role in RSV reinfection-associated immunopathophysiology (4). We showed that neonatal Th cells (i.e., Th1 and Th2 cells) express higher levels of IL-4R␣ than adult Th cells.…”

“…In this model, neonatal mice (Ͻ7 days old) are infected with RSV and various immunological parameters are measured. Notably, RSV-infected neonates mount limited Th1 (CD3 (4,6,8,9) and multifunctional Th (CD3 ϩ , CD4 ϩ , IFN-␥ ϩ , IL-4 ϩ ) cells (4), while the number of Th1 cells upon reinfection is equivalent to that in mice initially infected as adults. This biased Th2 response observed upon reinfection is associated with enhanced airway hyperreactivity (AHR), airway and lung eosinophilia, and mucus hyperproduction (4,6,8,9), all of which are consistent with the observations for infants from the 1960s clinical trials who died from community-acquired RSV infection (3).…”

“…Our and other laboratories have therefore developed a neonatal mouse model that better mimics RSV disease in infants (4)(5)(6)(7)(8)(9). In this model, neonatal mice (Ͻ7 days old) are infected with RSV and various immunological parameters are measured.…”