ST2: marker, activator and regulator of Th2 immunity? (2002)

Type 2 CD4+ T helper lymphocytes (Th2 cells) clearly play a critically important role in the chronic inflammatory response of asthma [1]. These cells preferentially secrete cytokines such as IL-4, 5, 9 and 13, expression of which correlates with the severity of clinical asthma [2]. In animal experimental models, allergen-responsive Th2 cells and cytokines such as IL-5 and IL-13 are able to induce inflammation and other phenotypic changes resembling allergic asthma [3–7]. Although a Th2 lymphocyte response dominates in the asthmatic airway, other inflammatory mechanisms also play important roles [8]. Increased cellular synthesis of the Th1 cytokine IFN-γ is demonstrable in asthmatics [9] and, like Th2 cytokines, has been related to disease severity [10]. Indeed, it has been suggested that interplay between Th1 and Th2 cells regulates aspects of the development of asthma and its exacerbations. Also of note is that several Th2 cytokines can be produced, albeit at lesser levels, by cells other than CD4+ T helper lymphocytes, e.g. mast cells [11–13]. Nevertheless, within this complex framework, understanding the mechanisms of activation of Th2 cells and the regulation of their cytokine products is highly relevant to the development of novel therapeutic approaches for asthma. Much attention has been focused on the possibility of inhibiting individual Th2 cytokines, their receptors or their signalling pathways. In animal models, administration of blocking antibodies or fusion peptides, as well as studies in gene-targeted animals, have yielded abundant data suggesting that these are promising approaches [14]. However, given the redundancy of cytokine activities and the complexity of the allergic inflammatory response, concentrating on single molecules or pathways may be a poor strategy. The limited number of reported human studies that have attempted to target individual Th2 cytokines have yielded mixed results [15, 16]. There have been fewer investigations of the potential of directly targeting Th2 cells. Suppressing the CD4+ T helper lymphocyte response non-selectively is very effective in animal models [17, 18] and T cell suppression is of demonstrable therapeutic benefit in patients with severe asthma [19, 20] but is clearly an extreme approach. Attempting to switch a Th2-dominated inflammatory response to a Th1 response seems unlikely to be an effective approach [21], especially in the long term. In fact there is now good evidence that Th1 cells and cells of mixed differentiation can not only contribute directly to the development of airway inflammation, but can also co-operate with Th2 cells in the induction of airway hyper-reactivity [22–24]. However, selective suppression of the Th2 response, either directly or indirectly, e.g. by disrupting mechanisms involved in cell– to–cell interaction, may be an attractive therapeutic option. It is in this context that identification of markers or functional regulators of Th2 cells is a high priority. The protein products of the T1/ST2 gene are appealing candidates in both of these categories. This gene belongs to the IL-1 receptor family and yields two mRNA isoforms, the longer of which codes for a membrane-bound protein and the shorter for a soluble form [25]. It was originally described as an early response gene of growth-stimulated fibroblastic cells [26] and is also expressed at a high level by mast cells [27]. However, the membrane-bound protein was subsequently identified as a specific marker for Th2 cells by differential display studies [28, 29]. Further investigations have suggested that it might best be characterized as a marker of effector Th2 cells rather than simply of Th2 cells [30], emphasizing its potential as a target for suppression of Th2-driven inflammation. As noted above, the T1/ST2 gene is related to the IL-1 receptor and the membrane-bound protein product of the longer mRNA, known as ST2L, is functionally important. Experiments using monoclonal antibodies or fusion proteins to inhibit ST2L consistently indicate that Th2-dependent inflammatory responses are abrogated by inhibition of ST2L and/or depletion of ST2L+ cells [28, 31, 32]. Data from studies of ST2-deficient mice are conflicting [33–35] but suggest that while ST2L can be bypassed by alternative mechanisms following multiple antigenic challenge, it probably plays a key role in the early events involved in the generation of Th2 responses. In this context, it is of interest that antigen-presenting dendritic cells, which are key regulators of Th polarization to antigens, appear to signal via, and to express a ligand for, ST2L [36]. Although a specific ligand for this receptor-like molecule has not yet been identified, it seems reasonable to conclude that ST2L is not only a marker but also an activator of Th2 cells. What then of the soluble form of ST2 derived from the short mRNA isoform? In a recent study, Oshikawa et al. demonstrated that serum levels of soluble ST2 were markedly elevated in asthmatic patients during acute attacks and that the magnitude of the elevation correlated with the reduction in peak expiratory flow, the severity of hypoxia and hypercapnia, as well as with increased levels of serum IL-5 [37]. They suggested that measurement of serum ST2 might be useful for monitoring airway inflammation during an acute exacerbation of asthma. In this issue of Clinical and Experimental Allergy, they have extended their investigations into the biological significance and role of this molecule [38]. Specifically, they examined the kinetics of expression of the short ST2 mRNA and of the increase in serum levels of soluble ST2 in a mouse model of allergic bronchopulmonary inflammation. They also undertook in vitro and in vivo experiments which demonstrated the potential of soluble ST2 to inhibit both Th2 cytokine production and the bronchopulmonary inflammatory response. Their results are intriguing and their paper raises important questions relating to this signalling system. The receptor-like ST2L may well be a cellular switch associated with induction of Th2 effector function, but what exactly is soluble ST2 doing? Previous work [29, 31] suggests that allergic inflammation can be inhibited by blockade of the binding of the unknown ligand for ST2L using a recombinant IgG fusion protein. This supports the contention of Oshikawa et al. that soluble ST2 might have an autoregulatory role, a contention that is supported by their experimental results from gene transfer studies. However, if signalling via ST2L is in fact only important during the induction of a Th2 response, then production of soluble ST2 in response to antigenic challenge when allergic sensitization has already been established seems unlikely to achieve much in terms of autoregulation. Consistent with this, in transgenic mice with high serum levels of a soluble ST2-Ig recombinant protein, which would be expected to bind to and block the putative ligand, there was minimal reduction in Th2-dependent pulmonary inflammation [35]. Another puzzle is the kinetics of release of soluble ST2 following in vivo antigenic challenge. If, as the authors suggest, this protein is not derived from shed ST2L but is instead independently regulated, the rapidity with which serum concentrations rise is indeed remarkable. Why should a potential inhibitor of the inflammatory response – which is in principle primarily a protective/defensive process – be released even before cellular recruitment or activation of Th2 cells is effectively underway? While the clinical relevance of soluble ST2 has been clearly demonstrated by Oshikawa et al. in their previous study [37], one is forced to conclude that at this point the functional role of the ST2L/soluble ST2 signalling system in Th2 immunity and the allergic response is unclear. Moreover, the cellular source and mechanisms of production of soluble ST2 remain undefined. The specific ligand for ST2L is also unidentified. The latter may well turn out to be another potential therapeutic target and its characterization will greatly facilitate evaluation of the contribution of products of the T1/ST2 gene to the pathogenesis – and conceivably the management – of allergic disease.