Respiratory Syncytial Virus Synergizes with Th2 Cytokines to Induce Optimal Levels of TARC/CCL17

Abstract

Respiratory syncytial virus (RSV) is a ubiquitous virus that preferentially infects airway epithelial cells, causing asthma exacerbations and severe disease in immunocompromised hosts. Acute RSV infection induces inflammation in the lung. Thymus- and activation-regulated chemokine (TARC) recruits Th2 cells to sites of inflammation. We found that acute RSV infection of BALB/c mice increased TARC production in the lung. Immunization of BALB/c mice with individual RSV proteins can lead to the development of Th1- or Th2-biased T cell responses in the lung after RSV infection. We primed animals with a recombinant vaccinia virus expressing either the RSV fusion (F) protein or the RSV attachment (G) protein, inducing Th1- and Th2-biased pulmonary memory T cell responses, respectively. After RSV infection, TARC production significantly increased in the vaccinia virus G-primed animals only. These data suggest a positive feedback loop for TARC production between RSV infection and Th2 cytokines. RSV-infected lung epithelial cells cultured with IL-4 or IL-13 demonstrated a marked increase in the production of TARC. The synergistic effect of RSV and IL-4/IL-13 on TARC production reflected differential induction of NFκB and STAT6 by the two stimuli (both are in the TARC promoter). These findings demonstrate that RSV induces a chemokine TARC that has the potential to recruit Th2 cells to the lung.

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

“…Eosinophils express CCR3 and CCR5 and are recruited into the lungs in part by CCL11 production after RSV challenge of vacvG-immunized mice [27,48,49]. In addition, RSV challenge of mice previously immunized with vacvG also results in a significant increase in the amount of CCL17 mRNA [50] and CCL22 protein [44] in the lung. These data suggest that chemokine production in the lung contributes to the development of pulmonary eosinophilia through the recruitment of both Th2 cells and eosinophils.…”

Virus-like particle vaccines containing F or F and G proteins confer protection against respiratory syncytial virus without pulmonary inflammation in cotton rats

“…[22][23][24] Both vv-G and vv-F vaccination of mice were shown to induce significant RSV disease of weight loss and histopathology after RSV challenge. 25 G-specific T cells were known to cause more severe RSV disease than F-specific T cells in mice. 26 Cotton rats with G VLP presented a tendency of causing a certain degree of lung inflammation around the airways, blood vessels, and interstitial spaces as well as eosinophils and mucus production compared with F VLP or FG VLP but much less than FI-RSV.…”

“…Mice primed with vv-G vaccines induced high levels of both Th2 IL-4 and Th1 IFN-g cytokines at high levels while vv-F primed mice showing high levels of IFN-g producing cells. 25 IFN-g has a dual role of RSV protection and RSV disease with high IFN-g T cell responses. 27 Th2 cytokines such as IL-4 have been implicated in the development of lung immunopathology whereas TNF-a inflammatory cytokine was shown to be responsible for weight loss in mice.…”

Expression and Function of CCL17 in Atopic Dermatitis

“…The promoter region of ccl17 contains several transcriptional regulation sites, like signal transducer and activator of transcription (STAT)6 binding sites and a nuclear factor kappa B (NF-κB) site (Liddiard et al, 2006;Liu et al, 2007;Monick et al, 2007;Nakayama et al, 2004;Wirnsberger et al, 2006). Expression of CCL17 is induced by the Th2 cytokines interleukin (IL)-4 and IL-13 via STAT6, and NF-κB activation occurs in response to TLR signaling.…”

“…Expression of CCL17 is induced by the Th2 cytokines interleukin (IL)-4 and IL-13 via STAT6, and NF-κB activation occurs in response to TLR signaling. In the case of CCL17 expression, both pathways appear to act synergistically (Monick et al, 2007). In addition, other cytokines, like tumor necrosis factor (TNF)-α, granulocyte/macrophage colony stimulating factor (GM-CSF), and TSLP have also been shown to upregulate CCL17 expression (Heijink et al, 2007;Imai et al, 1999;Liu et al, 2007;Soumelis et al, 2002;Wirnsberger et al, 2006;Xiao et al, 2003).…”