T-cell–intrinsic Tif1α/Trim24 regulates IL-1R expression on T H 2 cells and T H 2 cell-mediated airway allergy

The increasing number of patients presenting with severe asthma throughout the world present a clear unmet medical need. This study identified putative transcriptional regulators in T-helper 2 (T H 2) cells with the aim of identifying previously unidentified targets to inhibit T H 2-mediated allergy. Genetic deletion of Trim24 (tripartite motif-containing 24) in T cells showed that Trim24 was essential for T H 2-mediated allergy. Transcriptional analysis showed that Trim24 was required for many of the pathogenic properties of T H 2 cells and that IL-1–regulated signaling is compromised in Trim24 −/− cells. In vivo, in vitro, and in silico approaches identified a previously overlooked role for Trim24 in T H 2-mediated allergy and validate a combined approach to interrogate transcriptional datasets to identify new therapeutic targets to prevent allergy and asthma. There is a paucity of new therapeutic targets to control allergic reactions and forestall the rising trend of allergic diseases. Although a variety of immune cells contribute to allergy, cytokine-secreting αβ + CD4 + T-helper 2 (T H 2) cells orchestrate the type-2–driven immune response in a large proportion of atopic asthmatics. To identify previously unidentified putative targets in pathogenic T H 2 cells, we performed in silico analyses of recently published transcriptional data from a wide variety of pathogenic T H cells [Okoye IS, et al. (2014) Proc Natl Acad Sci USA 111(30):E3081–E3090] and identified that transcription intermediary factor 1 regulator-alpha ( Tif1α )/tripartite motif-containing 24 ( Trim24 ) was predicted to be active in house dust mite (HDM)- and helminth-elicited Il4 gfp + αβ + CD4 + T H 2 cells but not in T H 1, T H 17, or Treg cells. Testing this prediction, we restricted Trim24 deficiency to T cells by using a mixed bone marrow chimera system and found that T-cell–intrinsic Trim24 is essential for HDM-mediated airway allergy and antihelminth immunity. Mechanistically, HDM-elicited Trim24 −/− T cells have reduced expression of many T H 2 cytokines and chemokines and were predicted to have compromised IL-1–regulated signaling. Following this prediction, we found that Trim24 −/− T cells have reduced IL-1 receptor (IL-1R) expression, are refractory to IL-1β–mediated activation in vitro and in vivo, and fail to respond to IL-1β–exacerbated airway allergy. Collectively, these data identify a previously unappreciated Trim24-dependent requirement for IL-1R expression on T H 2 ce