Asthma represents the most common human chronic lung disease and is characterized by recurring symptoms of reversible airflow obstruction, bronchial hyperresponsiveness and pulmonary inflammation. Excessive activation of type-2 T helper (Th2) immune cells against inhaled environmental allergens contributes to the development of key asthma manifestations. In humans, the balance between suppressive T cells, including regulatory Tr1-like cells, and Th2 cells is decisive for the outcome of allergic responses. In fact, the protective effects of currently-employed immunotherapies are associated with the generation of highly-suppressive human Tr1-like cells. Hence, the identification of factors that can induce and/or expand human Tr1 cells represents an attractive therapeutic approach for the control of allergic responses and linked asthmatic disease.
In the present studies, using an experimental approach that combines in vitro priming of human naive T cells with ex vivo analysis of Th2 cells, we demonstrate that the cytokine activin-A instructs the generation of human Tr1-like T cells that effectively suppress allergen-driven responses in allergic and asthmatic individuals. Moreover, our mechanistic studies reveal that activin-A induces the activation of the transcription factor IRF4, which, along with the environmental sensor, AhR, control the differentiation and suppressive functions of human Tr1-like cells. Importantly, administration of human activin-A-induced Tr1-like cells in a humanized mouse model of allergic asthma confers protection against cardinal disease manifestations, in preventive and therapeutic regimes. Collectively, our studies unravel a novel biological function for activin-A in the generation of suppressive human Tr1-like cells that may be exploited for the control of allergic diseases.
Tousa S, Semitekolou M, Morianos I, Banos A, Trochoutsou AI, Brodie TM, Poulos N, Samitas K, Kapasa M, Konstantopoulos D, Paraskevopoulos G, Gaga M, Hawrylowicz CM, Sallusto F, Xanthou G.
Activin-A co-opts IRF4 and AhR signaling to induce human regulatory T cells that restrain asthmatic responses.
Proc Natl Acad Sci U S A. 2017 Mar 20. pii: 201616942. doi: 10.1073/pnas.1616942114. [Epub ahead of print]