Induction of Th-1 and Th-2 responses by respiratory syncytial virus attachment glycoprotein is epitope and major histocompatibility complex independent.

Respiratory syncytial virus (RSV) is the most common cause of viral lower respiratory tract infection worldwide. The disease is most severe in infants, children with underlying cardiopulmonary diseases, and children who are immunodeficient (8, 36). Recent evidence also implicates RSV as an important cause of respiratory tract infection in the elderly population (13, 26). Despite its importance as a human pathogen, there is currently no effective immunoprophylactic agent for this virus. Early attempts to vaccinate children with formalin-inactivated whole virions (FI-RSV) resulted in a paradoxically severe disease in these children when they were subsequently infected with the virus (10, 24). The mechanism(s) underlying the immunopathological effect of FI-RSV is not completely understood. Recent advances in the understanding of T-lymphocyte biology, in combination with the availability of animal models of RSV infection, have given a significant impetus to the study of the immune mechanisms operating during RSV infection. In particular, the role of cytokines produced by T cells has been clearly demonstrated. Induction of a Th-2-type response (high interleukin-4 [IL-4] and IL-5 production) has been shown to lead to the development of systemic illness (weight loss) as well as the development of pulmonary eosinophilia (1, 15–17, 29). Neutralization of IL-4, at the time of priming or viral challenge, in mice sensitized to FI-RSV results in the amelioration of systemic illness (11, 14, 37). Furthermore, the presence of eosinophils in the peripheral blood and in the lungs of children who had been vaccinated with FI-RSV and subsequently infected with RSV suggests the important role of Th-2 cytokines in the pathogenesis of this disease (24). In a murine model of RSV infection, the induction of Th-1- or Th-2-type cytokine responses is dependent on the sensitizing RSV antigen (2, 28, 34, 35). BALB/c mice primed with vaccinia virus expressing the attachment glycoprotein of RSV (RSV G) exhibit extensive recruitment of eosinophils into the lungs upon infection with RSV, indicating a strong Th-2 response (2, 28, 34, 35). Studies have suggested that the induction of Th-2 responses by this protein may be regulated by factors including the context of the protein during priming and the presence of immunomodulatory effectors, such as CD8+ T lymphocytes, during the differentiation and activation of CD4+ T cells (4, 17, 21, 23, 34, 37). However, the influence of the intrinsic properties of RSV G glycoprotein, especially the major histocompatibility complex (MHC)-peptide ligand complex recognized by effector CD4+ T cells on the induction of polarized cytokine responses to this protein has not been examined in detail. In the present study we analyzed in detail the cytokine profile of effector CD4+ T cells elicited by the RSV G glycoprotein in a murine model of RSV infection. We have found that RSV G glycoprotein primes for the simultaneous induction of Th-1- and Th-2-type responses after challenge infection of BALB/c (H-2d) mice with RSV and that both types of cytokine responses are produced by CD4+ T cells directed to a single immunodominant region of the G protein. This finding indicates that MHC-ligand complexes derived from RSV G glycoprotein do not direct the differentiation of CD4+ T lymphocytes towards a Th-1 or Th-2 phenotype. This view is further supported by findings with BALB/b (H-2b) mice, which differ from BALB/c mice at the MHC locus but have identical background genes. RSV G-sensitized BALB/b mice, when challenged with RSV, produce both Th-1- and Th-2-type cytokines directed to a single region of the RSV G glycoprotein. Finally, we began to evaluate the contribution of non-MHC genes to the development of pulmonary eosinophilia in this model. The implications of these findings for the immunopathogenesis of RSV and the development of vaccines are discussed.