A reciprocal relationship exists between Akt-mTOR activation and generation of induced regulatory T (Treg) cells. In the Journal of Experimental Medicine, Gomez-Rodriguez et al. identify the kinase Itk, a downstream mediator of T cell antigen receptor (TCR) signaling, as a critical regulator that influences Treg versus TH17 cell fate. Itk deficiency leads to preferential generation of Treg cells, even under conditions that favor TH17 cell differentiation. Loss of Itk reduces TCR- and interleukin-2 (IL-2)-mediated activation of phosphoinositide-3-kinase (PI(3)K)–Akt–mTOR–HIF-1α signaling, which is needed to promote TH17 cell fate. Itk acts indirectly to repress expression of Pten, which encodes a phosphatase that antagonizes PI(3)K-mediated generation of PtdIns(3,4,5)P3. Itk therefore couples TCR signaling to other activation pathways that regulate PtdIns(3,4,5)P3 abundance and influences cell fate decisions.

J. Exp. Med. (17 February 2014) doi:10.1084/jem.20131459