Monocyte chemotactic protein-induced protein 1 controls allergic airway inflammation by suppressing IL-5-producing T2 cells through the Notch/Gata3 pathway.

Background: Asthmatic and allergic inflammation is mediated by T2 cytokines (IL-4, IL-5, and IL-13). Although we have learned much about how T2 cells are differentiated, the T2 checkpoint mechanisms remain elusive.

Objectives: In this study we investigate how monocyte chemotactic protein-induced protein 1 (MCPIP1; encoded by the Zc3h12a gene) regulates IL-5-producing T2 cell differentiation and T2-mediated inflammation.

Methods: The functions of Zc3h12a CD4 T cells were evaluated by checking the expression of T2 cytokines and transcription factors in vivo and in vitro. Allergic airway inflammation of Zc3h12a mice was examined with murine asthma models. In addition, antigen-specific CD4 T cells deficient in MCPIP1 were transferred to wild-type recipient mice, challenged with ovalbumin (OVA) or house dust mite (HDM), and accessed for T2 inflammation.

Results: Zc3h12a mice have spontaneous severe lung inflammation, with an increase in mainly IL-5- and IL-13-producing but not IL-4-producing T2 cells in the lung. Mechanistically, differentiation of IL-5-producing Zc3h12a T2 cells is mediated through Notch signaling and Gata3 independent of IL-4. Gata3 mRNA is stabilized in Zc3h12a T2 cells. MCPIP1 promotes Gata3 mRNA decay through the RNase domain. Furthermore, deletion of MCPIP1 in OVA- or HDM-specific T cells leads to significantly increased T2-mediated airway inflammation in OVA or HDM murine models of asthma.

Conclusions: Our study reveals that MCPIP1 regulates the development and function of IL-5-producing T2 cells through the Notch/Gata3 pathway. MCPIP1 represents a new and promising target for the treatment of asthma and other T2-mediated diseases.