Data presented here demonstrate that ST2L is a stable cell surface marker expressed strongly on Th2s, but not Th1s. Furthermore, antibody against ST2L selectively lysed Th2s in vitro and enhanced Th1 response in vivo. Thus, anti-ST2L antibody increased resistance to L. major
infection in the highly susceptible BALB/c mice. It also exacerbated CIA in DBA/1 mice. These effects were accompanied by enhanced IFN-γ production and diminished IL-4/ IL-5 synthesis. It is likely that the antibody exerted its effect through direct depletion of Th2s in vivo and hence the regulation of Th1s by Th2s (1
), such that the balance is shifted towards Th1s. This is consistent with the observation that treatment with anti-ST2L antibody in the L. major
–infected mice did not significantly alter the production of IL-12, a cytokine principally secreted by macrophages and a major mediator of Th1 differentiation (30
). Such a mechanism would also explain the immediate effect of the antibody seen in the CIA model (Fig. ).
ST2L is not detectable on B cells, a macrophage cell line (J774), or a CD8+
cell line (CTLL) (data not shown). The developmental stage of Th2s at which ST2L expression occurs is currently unclear. However, the expression of ST2L is clearly associated with the production of IL-4 and IL-5. It has been reported that the transcription factor GATA-3 is necessary and sufficient for Th2 cytokine gene expression in CD4+
T cells (31
). Furthermore, the promoter region of ST2L contains the GATA consensus binding motif (32
). It is therefore possible that GATA-3 influences Th2 functions by directing the transcription of ST2L. The ontogeny of Th2s in relation to ST2L and the sequence of events leading to the induction of ST2L and Th2 cytokine production remain to be explored.
It is important to note that a soluble form (ST2, mol wt: 37-kD) without the trans
-membrane domain (10
) is also transcribed from the same gene by differential splicing, determined by the use of alternate promoters (13
). We have found that all Th2s expressing ST2L gene also express ST2 message (data not shown). The receptor-like nature of ST2L suggests the existence of a ligand that is yet to be identified. It may be that the membrane bound form (ST2L) and the soluble form (ST2) act as regulators of Th2 functions. Furthermore, they should serve as important biologically relevant tools for investigating gene regulation for the expression of a trans
-membrane versus a secreted form of a protein.
The in vivo effect of anti-ST2L antibody in mice suggests that selective modulation of ST2L expression could have considerable therapeutic potential. The close association of ST2L expression with IL-4/IL-5 production suggests that the membrane-bound ST2L molecule could be a potentially important therapeutic target for allergic responses such as asthma. ST2L is present in humans (34
) and its relevance in human T cell functions is currently being addressed.
In conclusion, we have identified a stable cell surface marker distinguishing Th2s from Th1s. Furthermore, an antibody against this molecule has a range of biological effects in vivo including infection and inflammation. Thus, this marker will not only facilitate functional analysis of Th1 and Th2 interaction, it may also be a potential target for therapeutic intervention for some of the important diseases.