In addition to the CD28 superfamily, the tumour necrosis factor receptor family consists of an increasing number of receptor–ligand pairs.36 With regard to Th2 cell differentiation and polarization two members have received
attention, OX40 and glucocorticoid-induced tumour necrosis factor receptor-related Kinase Inhibitor Library cell assay protein (GITR). OX40 is up-regulated on recently activated T cells following CD40 ligand stimulation. OX40 ligand (OX40L) -expressing DCs, but not other cells, provides a critical return signal to the Th2 survival or expansion.37 For initial priming of T cells OX40 does not appear to be required, indicated by experiments using OX40L-deficient DCs. However, for proliferation,
re-activation of effector function and cytokine check details secretion, OX40 ligation was required. GITR is also up-regulated on activated αβ+ CD4+ Th cells and regulatory T cells. Super-physiological stimulation through GITR can enhance Th2 cell frequency,38 exacerbate Th2-associated airway inflammation39,40 and also potentiate Th1 cell responses.40 However, in the absence of GITR ligation Th2 cells still develop following helminth infection.38 GITR may therefore be a redundant co-stimulatory molecule for Th2 development in vivo, and may act to fine-tune Th2 cell differentiation and expansion, along with other co-stimulatory/inhibitory signals. Finally, the third families of co-stimulatory molecules involved in T-cell activation are the Notch-Jagged/Delta interactions. Of the four Notch receptors (Notch 1–4) and five ligands (Jagged 1, 2 and Delta 1, 3 and 4) several interactions have been studied in the context of Th2 differentiation. In two independent studies using genetic manipulation, Notch-signalling in the T cell was found to target GATA-3, independent of exogenous IL-4.41,42 Whereas Jagged two does not appear to be the necessary ligand for Notch,43 Jagged-144 and Delta-445,46 both appear to enhance Th2 responses. However, Delta-1-expressing
and Delta-4-expressing DCs can also inhibit Th2 differentiation.47 The precise pairing of ligands 3-mercaptopyruvate sulfurtransferase and receptors is still not clear and may involve a combination of several ligands and receptors playing an appropriate Th2 ‘chord’. In summary, the complete narrative regarding co-stimulation, beyond the above-mentioned interactions, for Th2 cell differentiation may never be fully realized, but so far we can certainly enhance and inhibit Th2 cell differentiation, and differentiate or disarm Th2 effector functions when necessary. As more advanced imaging and genetic tools become commonplace, our understanding of Th2 cells and the co-stimulatory requirements will become more refined and in course more able to be manipulated. The third signal received, not in this particular order, is provided by soluble cytokines.