On the tumultuous shores of the intestinal epithelium, TSLP keeps the peace. When faced with a threat, the cytokine not only triggers a protective Th2 response, it also helps keep intestinal inflammation in check, suggest Taylor et al. on page 655.

In the past few years, some researchers have classified TSLP as a “master regulator” of the Th2 response. However, that title may be premature, even though overexpression of the cytokine in pulmonary tissue and skin cells result in Th2-induced asthma and dermatitis. As Th2 responses also defend the body against worm infections, Taylor et al. turned to the gut to see if TSLP could be more than a harbinger of Th2-driven malady.

As predicted, mice could neither mount a Th2 response nor clear a worm infection when TSLP or its receptor were blocked. In fact, the intestinal inflammation in these mice was abnormally severe, most likely due to abundant expression of inflammatory cytokines such as IFNγ, IL-17, and IL-12/23p40.

The abundance of these cytokines meant that the ratio of CD4+ effector T cells was skewed away from Th2. And the aberrant expression of IFNγ, which suppresses Th2 cell differentiation, presumably maintains this imbalance. Indeed, neutralization of IFNγ rescued the Th2 response and restored anti-worm immunity in TSLP-deficient mice. TSLP might normally suppress Th1 responses by acting directly on dendritic cells (DCs), as treating activated DCs with TSLP hampered production of the Th1-promoting cytokine IL-12.

TSLP also proved important for ameliorating inflammation in a mouse model of colitis, suggesting a general anti-inflammatory role for TSLP in the gut.

By exposing TSLP's brighter side, the authors provide an explanation for why this protein may have been maintained during evolution. If TSLP did nothing more than fire up asthma-inducing Th2 cells, why would it still exist, reasons lead author David Artis. Perhaps it acquired the ability to both drive Th2 responses and control inflammation in the gut where these responses go hand-in-hand. TSLP seems to maintain a role in controlling inflammation in humans as well. In a recent survey of Crohn's disease patients, intestinal inflammation was worse in those with less TSLP.