The deubiquitinase CYLD controls protective immunity against helminth infection by regulation of Treg plasticity

Abstract Background Type 2 immunity can be modulated by regulatory T cell (Treg) activity. It has been suggested that the deubiquitinase CYLD plays a role in the development or function of Treg cells implying it could be important for normal protective immunity where type 2 responses are prevalent. Objective We sought to investigate the role of CYLD in Treg function and T helper type (Th2) immune responses under steady state conditions and during helminth infection. Methods Foxp3-restricted CYLD conditional knockout mice (cKO) were examined in mouse models of allergen-induced airway inflammation and Nippostrongylus brasiliensis infection. We performed multiplex magnetic bead assays, flow cytometry and qPCR to understand how a lack of CYLD affected cytokine production, homing and suppression in Tregs. Target genes regulated by CYLD were identified and validated by microarray analysis, co-immunoprecipitation, shRNA knockdown, and transfection assays. Results Treg-specific CYLD knockout mice showed severe spontaneous pulmonary inflammation with increased migration of Treg cells into the lung. CYLD-deficient Treg cells furthermore produced high levels of interleukin-4 (IL-4) and failed to suppress allergen-induced lung inflammation. Supporting this, the cKO mice displayed enhanced protection against N. brasiliensis infection by contributing to type 2 immunity. Treg conversion into IL-4 producing cells was due to augmented MAPK and NF-κB signaling. Moreover, Scinderin, a member of the actin-binding gelsolin family, was highly upregulated in CYLD-deficient Treg cells, and controlled IL-4 production through forming complexes with MEK/ERK. Correspondingly, both excessive IL-4 production in vivo and the protective role of CYLD-deficient Treg cells against N. brasiliensis were reversed by Scinderin ablation. Conclusions Our findings indicate that CYLD controls type 2 immune responses by regulating Treg conversion into Th2-like effector cells, which potentiates parasite resistance.