Distinct types of lung disease caused by functional subsets of antiviral T cells.

Abstract

SummaryT cells appear to play a central role in viral bronchiolitis, but the effects of different functional and phenotypic subgroups ofT cells have not been defined. To test the activities ofT cells recognizing individual proteins of respiratory syncytial (RS) virus, virus-specific T cell lines were produced from mice primed by scarification with recombinant vaccinia viruses expressing the major surface glycoprotein (G), fusion protein (F) or second matrix (22K) protein of KS virus. As previously reported, the in vitro characteristics of these cells are predetermined by the choice of KS virus protein: 22K-specific cells are predominantly class I-restricted cytolytic CD8 + cells; F-specific cells, a mixture of cytolytic CD8 + cells and CD4 + cells with a T helper 1 cell (Thl) cytokine secretion profile, whereas those from G-sensitized mice are almost exclusively CD4 + , with Th2 characteristics. Mice infected intranasally with RS virus showed mild illness and recovered fully, but developed respiratory distress after intravenous injections of T cells. Dose-for-dose, infected mice receiving G-specific cells suffered the most severe (sometimes fatal) illness, characterized by lung hemorrhage, pulmonary neutrophil recruitment (shock lung) and intense pulmonary eosinophilia. This disease was further enhanced by coinjection of 22K-specific cells, which alone caused mild shock lung without eosinophilia. F-specific cells caused minimal enhancement of pathology and had little or no effect on the disease caused by G-specific cells. Each cell line reduced lung virus titer and combined injections of G-and 22K-specific cells eliminated infection completely. The in vitro characteristics of these antiviral T cell lines therefore predict the pathological effects in vivo. Moreover, different forms of viral bronchiolitis can be caused by functionally distinct types of activated T cell.

Intranasal immunisation with inactivated RSV and bacterial adjuvants induces mucosal protection and abrogates eosinophilia upon challenge

“…Not only does this factor not alter protection of mice against viral replication, it might also contribute to the reduced numbers of infiltrating eosinophils observed after RSV challenge. Indeed, RSVspecific CD8 + T cells have been implicated in the pathology linked with both neutrophil and eosinophil infiltrates upon infection [16,17]. These elements are further evidence that, while CTL might be the main factor contributing to the resolution of primary RSV infection, they are dispensable and possibly deleterious in vaccine-induced protection against re-infection and lung pathology.…”

“…Several studies have demonstrated the ability of iRSV to prime for a Th2 response, thus leading to an inappropriate response, highlighted by substantial eosinophilia in the lung after RSV challenge at least in animal models. Previous animal studies have delivered the iRSV mainly by the intramuscular route, although other studies have delivered vaccinia virus constructs carrying the RSV G protein by scarification at the base of the tail [14][15][16]. These methods of immunisation prime for a Th2 response in the lung after RSV challenge.…”

Detection and quantitation of eosinophils in the murine respiratory tract by flow cytometry

“…In this model, mice previously immunized with a recombinant vaccinia virus expressing the gene encoding the RSV-G glycoprotein will, upon challenge intranasal RSV infection, develop a CD4 + T cell Th2 type response in the lungs characterized by elevated levels of eosinophils in the BAL fluid and lung parenchyma (Openshaw et al 1992), (Alwan et al 1994), (Varga et al 2000).…”

“…chicken egg albumin administration), and in murine models of respiratory virus infection where type II CD4 + T cell responses play a prominent role [e.g. challenge Respiratory Syncytial Virus (RSV) infection of immune mice (Openshaw et al 1992), (Srikiatkhachorn and Braciale 1997), (Johnson et al 1998), (Alwan et al 1994), (Varga et al 2000), (Varga et al 2001)]. …”

Polylactide-co-glycolide (PLG) microparticles modify the immune response to DNA vaccination

“…Asthma is characterised by a bias towards Th2 responses, associated frequently with airway eosinophilia. In a mouse model of RSV disease, sensitisation with recombinant vaccinia expressing the viral glycoprotein G primes for a strong Th2 biased immune response that causes lung eosinophilia during intranasal infection with RSV [10]. G can be mutated at the second initiation codon to prevent secretion of the glycoprotein, and sensitisation with recombinant RSV expressing only the membrane bound (non-secreted) form of the G protein induces significantly less of an eosinophilic response during RSV challenge [11].…”