IL-13 Is Sufficient for Respiratory Syncytial Virus G Glycoprotein-Induced Eosinophilia After Respiratory Syncytial Virus Challenge

Abstract

Although well studied in settings of helminth infection and allergen sensitization, the combined contributions of IL-4 and IL-13 and their signaling pathways in models of viral pathogenesis have not been reported. Using a murine model of respiratory syncytial virus (RSV) infection, we evaluated the contribution of IL-13, alone and in conjunction with IL-4, during immunization with recombinant vaccinia virus expressing RSV G glycoprotein (vvGs) or with formalin-inactivated RSV (FI-RSV). We showed that both IL-4 and IL-13 activity must be inhibited to modulate G-specific responses resulting in severe RSV-induced disease. Inhibition of IL-4 or IL-13 activity alone had minimal impact on disease in vvGs-immunized mice. However, treatment of IL-4-deficient mice with IL-13Ra during vvGs immunization reduced IL-5, IL-13, and eotaxin production and pulmonary eosinophilia after RSV challenge. In contrast, FI-RSV-induced immune responses were diminished when either IL-4 or IL-13 activity was blocked. After RSV challenge, these type 2 T cell responses were also diminished in vvGs-primed IL-4Rα-deficient mice. Our data suggest that secreted vvGs uses mechanisms requiring signaling through the IL-4Rα-chain by either IL-4 or IL-13 for induction of eosinophilia and is the first description of the relative contributions of IL-4, IL-13, and their receptors in viral pathogenesis.

Characterization of Recombinant Respiratory Syncytial Viruses with the Region Responsible for Type 2 T-Cell Responses and Pulmonary Eosinophilia Deleted from the Attachment (G) Protein

“…RSV infection was shown to upregulate the expression of nerve growth factor and its receptors (26), and the presence of G protein was associated with the secretion of substance P, a tachykinin neuropeptide (54). It was also recently demonstrated that IL-13 alone was adequate for G protein-induced eosinophilia (30). Thus, through secretion of cytokines such as IL-13, type 2 T cells in the lungs against G protein could contribute directly to airway hyperresponsiveness, mucus hypersecretion, and inflammation (12,60).…”

Overcoming T-Cell-Mediated Immunopathology to Achieve Safe Respiratory Syncytial Virus Vaccination

“…In contrast to FI-RSV immunized mice, IL-13, but not IL-4, is necessary for the development of pulmonary eosinophilia in vacvG-immunized mice [27,44]. In addition, it has also been shown that treatment of vacvG-immunized mice with recombinant IL-12, a cytokine important in the differentiation of Th1 cells, reduces pulmonary eosinophilia [45,46].…”

“…The G 183-195 -specific memory CD4 T cell response is comprised of predominately Th1 (IFN-γ and/or tumor necrosis factor-α (TNF-α)-producing) cells with a small proportion of Th2 (IL-4-, IL-5-, and/or IL-13-producing) cells [21,23,27,34,37,[40][41][42]. Interestingly, the diversity of the CD4 T cells capable of recognizing the G protein of RSV appears limited because the majority of RSV G 183-195 -specific memory CD4 T cells express the Vβ14 T cell receptor on their surface [41].…”

“…IL-4-deficient mice immunized with FI-RSV fail to develop pulmonary eosinophilia after RSV challenge establishing a critical role for IL-4 in this process [23,27]. In addition, depletion of IL-13 prior to and after immunization of mice with FI-RSV also inhibits the development of pulmonary eosinophilia [27]. These data indicate that the Th2-associated cytokines IL-4 and IL-13 both promote the development of pulmonary eosinophilia upon RSV challenge of FI-RSV-immunized mice and suggest that the children vaccinated with FI-RSV underwent a memory Th2 response after contracting a natural RSV infection.…”

“…The memory CD4 T cell response is comprised of both Th1 and Th2 cells as demonstrated by the detection of the Th1-associated cytokine interferon-γ (IFN-γ) and the Th2-associated cytokines interleukin-4 (IL-4), IL-5, and IL-13 in the lung after RSV challenge of FI-RSV-immunized mice [21,22,26]. IL-4-deficient mice immunized with FI-RSV fail to develop pulmonary eosinophilia after RSV challenge establishing a critical role for IL-4 in this process [23,27]. In addition, depletion of IL-13 prior to and after immunization of mice with FI-RSV also inhibits the development of pulmonary eosinophilia [27].…”