Interleukin-21-Producing CD4+ T Cells Promote Type 2 Immunity to House Dust Mites

• House dust mites induce potent IL-21 production by Tfh cells in lymphoid organs
• IL-21+ cells are distinct from Th2 cells and migrate to the lung tissue and airway
• IL-21R provides cell-intrinsic cues for Th2 cell functions
• IL-21 synergizes with innate signals to promote adaptive Th2 cell responses

SummaryAsthma is a T helper 2 (Th2)-cell-mediated disease; however, recent findings implicate Th17 and innate lymphoid cells also in regulating airway inflammation. Herein, we have demonstrated profound interleukin-21 (IL-21) production after house dust mite (HDM)-driven asthma by using T cell receptor (TCR) transgenic mice reactive to Dermatophagoides pteronyssinus 1 and an IL-21GFP reporter mouse. IL-21-producing cells in the mediastinal lymph node (mLN) bore characteristics of T follicular helper (Tfh) cells, whereas IL-21+ cells in the lung did not express CXCR5 (a chemokine receptor expressed by Tfh cells) and were distinct from effector Th2 or Th17 cells. Il21r−/− mice developed reduced type 2 responses and the IL-21 receptor (IL-21R) enhanced Th2 cell function in a cell-intrinsic manner. Finally, administration of recombinant IL-21 and IL-25 synergistically promoted airway eosinophilia primarily via effects on CD4+ lymphocytes. This highlights an important Th2-cell-amplifying function of IL-21-producing CD4+ T cells in allergic airway inflammation.

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