Abstract
Memory Th2 cells are important in the pathogenesis of allergic responses including asthma, orchestrating recruitment of eosinophils and other inflammatory cells. Members of the tumor necrosis factor (TNF) receptor superfamily have emerged as key contributors to T cell activity, and therefore we investigated whether the engagement of the herpesvirus entry mediator (HVEM) on T cells by the TNF family molecule LIGHT controls Th2 mediated lung inflammation. Using systems where either HVEM or LIGHT are only defective on responding antigen-specific T cells, we demonstrated that the presence of HVEM on T cells is indispensible for the generation and persistence of Th2 memory cells and for allergen-induced Th2 lung inflammation, despite having a limited effect on early Th2 effector responses. Using adoptive co-transfer experiments we demonstrate that HVEM-LIGHT interaction on CD4 T cells can support longevity of T cells and promote memory generation. We also observed reduced activity of protein kinase B (PKB/Akt) and NF-κB in HVEM-deficient effector CD4 T cells, correlating with their poor survival. Furthermore, expression of an active form of PKB in HVEM-deficient T cells rescued Th2 cell survival in vivo, and restored lung inflammation in recall responses. Collectively, our results demonstrate a critical role of HVEM signals in the pathogenesis of Th2 derived lung inflammation and suggest that blocking of HVEM-LIGHT interactions could be a novel therapeutic target for asthma