We now know that TSLP is highly expressed by skin keratinocytes and airway epithelial cells during allergic inflammation (), but how TSLP expression is triggered in these cells—by allergen exposure or virus infection—remains unclear. As the expression of RXRs in skin keratinocytes may actively suppress TSLP production under normal physiological conditions, further studies on the regulation of these receptors may provide important clues as to how allergen or viral infection triggers TSLP production.
Figure 2. Pathophysiology of TSLP in allergic inflammation. Insults from allergens or viruses trigger mucosal epithelial cells or skin cells (keratinocytes, fibroblasts, and mast cells) to produce TSLP (step 1). TSLP activates immature DCs (step 2). TSLP-activated (more ...)
TSLP instructs mDCs to induce inflammatory Th2 cells in two ways (). First, TSLP induces DC maturation without driving the production of the Th1-polarizing cytokine IL-12, thus creating a Th2-permissive microenvironment. Second, TSLP induces the expression of OX40L on DCs, which directly triggers the differentiation of inflammatory Th2 cells. The signaling pathway that is triggered by TSLP and leads to this unique Th2 phenotype is unknown, but it appears to involve STAT5 activation, independent of the classical NF-κB and myD88 signaling pathways.
OX40L signaling has several important features. It triggers Th2 polarization independent of IL-4, promotes TNF production, and inhibits IL-10 production by the developing Th2 cells, but only in the absence of IL-12. In the presence of IL-12, OX40L signaling instead promotes the development of Th1 cells that, like inflammatory Th2 cells, produce TNF, but not IL-10. This finding may help explain why blocking OX40–OX40L interaction reduces the severity of Th1-mediated autoimmune diseases (29
)—the reason some immunologists are reluctant to accept OX40L as a Th2 polarizing factor. We now believe that this inhibition of Th1-induced pathology is caused by the increased production of the immunosuppressive cytokine IL-10 and the decreased production of the inflammation-promoting cytokine TNF that results from blocking OX40–OX40L interactions.
Based on these recent studies, we propose the subdivision of Th2 cells into inflammatory Th2 cells that produce high levels of TNF but little IL-10, and conventional Th2 cells that produce little TNF but high levels of IL-10. Inflammatory Th2 cells, but not conventional Th2 cells, may be involved in allergic inflammatory diseases.
Our initial finding that epithelial cell–derived TSLP triggers DC-mediated inflammatory Th2 responses in humans, together with the exiting in vivo studies reported in the last few months, suggest that TSLP represents a master switch of allergic inflammation at the epithelial cell–DC interface. TSLP should therefore be considered as a target for immunological intervention in the treatment of allergic diseases.