RSV bronchiolitis, γδ T cells and asthma: are they linked?

Most of our lymphocytes are not sitting in our lymphoid organs but lining mucosal surfaces. It makes sense that this should be so, as most infections come in either through the gut, lung or genital tract. T cells expressing the γδ T cell receptor have a particular association with mucosal epithelial surfaces, but what they do is still largely enigmatic [1]. Although a major component of the T cell population in cattle and sheep, γδ T cells are relatively scarce in the circulation and peripheral lymphoid tissues of most mammals. During ontology, γδ T cells appear before αβ T cells and are the first to colonize the peripheral tissues of the lung, intestine and skin [2]. Whereas αβ T cells recognize peptide fragments of antigen presented by MHC proteins, many systemic human γδ T cells recognize small non-peptidic molecules, and others appear to recognize non-classical MHC (e.g. CD1) [3]. They seem to have a protective role against intracellular microbial infections, particularly mycobacteria and protozoa. More controversially, they may also protect against cutaneous carcinomas [4] and perhaps suppress αβ T cell-mediated inflammation in allergic states [5].

In this issue of Clinical and Experimental Immunology, Aoyagi et al. report a study of 15 infants with severe lung infections due to respiratory syncytial virus (RSV) and seven with reovirus infections of the gut. They found that mitogen-stimulated γδ T cells from the peripheral blood of infants with acute RSV infection produced significantly less IFN-γ and more IL-4 than γδ T cells from infants with acute reovirus infection. During convalescence, the percentage of γδ T cells producing IFN-γ increased in seven children who recovered fully but failed to do so in eight who developed postbronchiolitic wheezing. There was no significant difference in the percentage that produced IL-4, but the numbers were small. They conclude that cytokine production by γδ T cells during acute RSV infection may play an important role in the development of recurrent wheeze after RSV infection.

These are novel, intriguing and rather surprising results. They raise questions about the role of γδ T cells in viral infections, asthma and atopic disease. This is not the first time such questions have been raised: in the normal, non-allergic mucosa γδ T cells comprise 5–10% of CD3⁺ cells, rising to between 20 and 30% in allergic rhinitis patients [6,7]. Such γδ T cells produce type 2 cytokines (including IL-4 and Il-13) and may induce T cells to switch to IgE production [8]. An increase in the number of γδ T cells producing type 2 cytokines has also been reported in the bronchial lavage of patients with allergic asthma [4], and after segmental allergen challenge in mild atopic asthmatics [9].

Most studies of antiviral T cells have focused on the role of conventional αβ T cells. In TcR β^–/– mice, intraperitoneal infection with vaccinia virus causes a large increase in the number of γδ T cells in the peritoneal exudate, reflected by a rise in the number of cytolytic γδ cells making IFN-γ in the peripheral blood. In TcR δ^–/– mice, spleen and footpad titres of vaccinia increase 10–100-fold on days 3–4 of infection, suggesting that they have a role in control of early viral infection in this model. By contrast, the TcR β^–/– mice had major problems in controlling viral replication from day 12, after which viral titres increased with fatal consequence [10,11]. Although there is circumstantial evidence that γδ cells play a role in human EBV [12] and CMV infections, there have been no studies demonstrating an important role for γδ T cells in defence against lung viruses. In cattle, γδ T cells do not appear to contribute to the clearance of RSV [13], and in the mouse model the epithelial T cell response to RSV infection is dominated by αβ T cells, with very few γδ cells being found [14]. This makes the findings by Aoyagi et al. particularly intriguing, especially because of the suggestion that children who develop recurrent wheeze after RSV bronchiolitis show a quite remarkable inability to increase IFN-γ production by their peripheral γδ T cells during convalescence.

These results suggest an important role for γδ T cells not only in the pathogenesis of acute RSV disease in human infants, but also in the development of recurrent wheezing after bronchiolitis. Clearly, different types of wheezing disorder can arise by distinct immunopathogenic mechanisms. What is true of post viral wheeze in young children is not at all a guide to what happens in atopic asthma in older children and young adults, and both are certain to be due to different pathogenic mechanisms from nonatopic ‘intrinsic’ asthma of later onset. However, many of the patients in the current study were from atopic families and it is important to recognize that this study involved very few patients. Moreover, the authors used mitogen rather than specific antigens to drive cytokine production and only studied IL-4 and IFN-γ. The convalescent responses were studied in the RSV group but not in the reovirus-infected children. Perhaps most importantly, it is not clear if the differences they found reflect the different sites of infection of reovirus (the gut) and RSV (the lung) or whether different viruses generating contrasting and specific effects on cytokine production by γδ T cells. Despite these caveats, the authors are to be congratulated on their novel findings. This study raises new questions about the role of γδ T cells not only in influencing patterns of cytokine production by subsequently recruited αβ T cells, but also about their possible regulatory role in the pathogenesis of T cell-mediated inflammatory disorders.

What could explain Aoyagi's et al.'s observations? Perhaps too many theories should not be generated from an unconfirmed report on a small number of patients, but several possibilities suggest themselves. First, pulmonary cytolytic γδ T cells could contribute to limiting viral replication in the early stages of RSV bronchiolitis, reducing the severity and duration of viral replication. Perhaps those patients with higher levels of IFN-γ and cytolytic activity wheeze less once they have recovered from bronchiolitis because the viral infection is terminated more quickly. Secondly, the recruitment of γδ T cells with type 2 cytokine profiles could establish a cytokine environment in the lung that is subsequently reflected by αβ T cells with a Th2 profile. These could form a memory pool not only for RSV, but also for other viral and non-viral challenges to the lung. The pattern of cytokine production in the lung could be established in part by the early cytokine expression by γδ cells in infancy during the first major infectious challenge that they encounter.

What are the main things we have learnt about RSV disease? First, it has a range of possible pathogenic pathways; secondly, the immune response evolves with time, and any study that only looks at a limited time window is potentially flawed; thirdly, different anatomical locations reveal different immune components and lastly, the most numerous cells may not be the prime movers. This last point highlighted by Aoyagi et al. γδ Cells may be a small population, but could have a big effect on what follows. As with many concepts in immunology, γδ T cells go through cycles of fashion. The current study contributes to the rising tide of information about the role of γδ T cells in everyday diseases. Clearly, they are not just an arcane evolutionary echo but a subset to be watched.