Interleukin 4 promotes the development of ex-Foxp3 Th2 cells during immunity to intestinal helminths

• DOI: 10.1084/jem.20161104
• Publication Date: 2017-05-15T14:10:12Z
• Authors: Victoria S. Pelly; Stephanie M. Coomes; Yashaswini Kannan; Manolis Gialitakis; Lewis J. Entwistle; Jimena Perez-Lloret; Stephanie Czieso; Isobel S. Okoye; Dominik Rückerl; Judith E. Allen; Frank Brombacher; Mark S. Wilson
• Keywords: 0301 basic medicine; Nematospiroides dubius; Gene Expression Profiling; Immunity; Cell Polarity; Forkhead Transcription Factors; Adoptive Transfer; T-Lymphocytes, Regulatory; Receptors, Interleukin-4; 3. Good health; Intestines; Mice, Inbred C57BL; 03 medical and health sciences; Th2 Cells; Animals; Interleukin-4; Research Articles; Signal Transduction; Strongylida Infections

Immunity to intestinal helminth infections requires the rapid activation of T helper 2 cells (Th2 cells). However, simultaneous expansion of CD4+Foxp3+ regulatory T cells (T reg cells) impedes protective responses, resulting in chronic infections. The ratio between T reg and effector T cells can therefore determine the outcome of infection. The redifferentiation of T reg cells into Th cells has been identified in hyperinflammatory diseases. In this study, we asked whether ex–T reg Th2 cells develop and contribute to type-2 immunity. Using multigene reporter and fate-reporter systems, we demonstrate that a significant proportion of Th2 cells derive from Foxp3+ cells after Heligmosomoides polygyrus infection and airway allergy. Ex-Foxp3 Th2 cells exhibit characteristic Th2 effector functions and provide immunity to H. polygyrus. Through selective deletion of Il4ra on Foxp3+ cells, we further demonstrate IL-4 is required for the development of ex-Foxp3 Th2 cells. Collectively, our findings indicate that converting T reg cells into Th2 cells could concomitantly enhance Th2 cells and limit T reg cell–mediated suppression.